Gastroenterology

Gastroenterology

Volume 158, Issue 1, January 2020, Pages 123-136
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Efficacy and Safety of Peppermint Oil in a Randomized, Double-Blind Trial of Patients With Irritable Bowel Syndrome

https://doi.org/10.1053/j.gastro.2019.08.026Get rights and content

Background & Aims

Peppermint oil is frequently used to treat irritable bowel syndrome (IBS), despite a lack of evidence for efficacy from high-quality controlled trials. We studied the efficacy and safety of small-intestinal–release peppermint oil in patients with IBS and explored the effects of targeted ileocolonic-release peppermint oil.

Methods

We performed a double-blind trial of 190 patients with IBS (according to Rome IV criteria) at 4 hospitals in The Netherlands from August 2016 through March 2018; 189 patients were included in the intent-to-treat analysis (mean age, 34.0 years; 77.8% female; 57.7% in primary care), and 178 completed the study. Patients were randomly assigned to groups given 182 mg small-intestinal–release peppermint oil, 182 mg ileocolonic-release peppermint oil, or placebo for 8 weeks. The primary endpoint was abdominal pain response, as defined by the US Food and Drug Administration: at least a 30% decrease in the weekly average of worst daily abdominal pain compared with baseline in at least 4 weeks. The co-primary endpoint was overall relief of IBS symptoms, as defined by the European Medicines Agency. Secondary endpoints included abdominal pain, discomfort, symptom severity, and adverse events.

Results

Abdominal pain response did not differ significantly between the peppermint oil and placebo groups: 29 of 62 patients in the small-intestinal–release peppermint oil group had a response (46.8%, P = .170 vs placebo), 26 of 63 patients in the ileocolonic-release peppermint oil group had a response (41.3%, P = .385 vs placebo), and 22 of 64 patients in the placebo group had a response (34.4%). We did not find differences among the groups in overall relief (9.7%, P = .317 and 1.6%, P = .351 vs 4.7% for placebo). The small intestinal peppermint oil did, however, produce greater improvements than placebo in secondary outcomes of abdominal pain (P = .016), discomfort (P = .020), and IBS severity (P = .020). Adverse events, although mild, were more common in both peppermint oil groups (P < .005).

Conclusions

In a randomized trial of patients with IBS, we found that neither small-intestinal–release nor ileocolonic-release peppermint oil (8 weeks) produced statistically significant reductions in abdominal pain response or overall symptom relief, when using US Food and Drug Administration/European Medicines Agency recommended endpoints. The small-intestinal–release peppermint oil did, however, significantly reduce abdominal pain, discomfort, and IBS severity. These findings do not support further development of ileocolonic-release peppermint oil for treatment of IBS. Clinicaltrials.gov, Number: NCT02716285.

Section snippets

Study Design, Setting, and Patients

The PEppeRmint Oil for the treatment of Irritable Bowel Syndrome: optimizing therapeUtic strAtegies using targeted DElivery (PERSUADE) study was a randomized, double-blind, placebo-controlled trial and was performed in 4 Dutch hospitals: 1 academic with a combined secondary and tertiary care function (Maastricht University Medical Center+ [MUMC+]) and 3 secondary care hospitals (Hospital Gelderse Vallei, Ede; Alrijne Hospital, Leiden; and Medical Center Leeuwarden). The study protocol was

Patient Disposition, Demographics, and Baseline Characteristics

Between August 2016 and March 2018, 622 patients were screened for participation in this study, of whom 190 were randomized (Supplementary Figure 2). One patient was erroneously randomized (ie, without having a mean worst abdominal score of more than 3 during the pretreatment period) and was excluded from further analyses. Therefore, the modified ITT population consisted of 189 patients. Baseline characteristics are shown in Table 1 and were balanced across treatment groups (mean overall age,

Discussion

To our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial of peppermint oil in patients with Rome IV-defined IBS. It showed that neither small-intestinal–release nor ileocolonic-release peppermint oil led to a statistically significant reduction in abdominal pain or increase in global relief based on the prespecified primary outcome measures as defined by FDA and EMA guidelines. Small-intestinal–release, but not ileocolonic, peppermint oil, however, did

Acknowledgments

We thank all patients with IBS who participated in the PERSUADE study; N. C. P. Aendekerk, D. J. P. A. Janssen, A. B. A. Quanjel, G. Van Hooff, G. L. Homans, A. J. Van de Vendel, M. G. Oosterveer, A. Westendorp-Ijdema, L. Vork, H. J. A. Jebbink, and G. J. Tack-Blokker for their practical assistance and help with recruitment during the study; the Dutch IBS Patient Federation for its cooperation; MEMIC (the center for data and information management at MUMC+) for the development of the electronic

References (46)

  • M. Otten et al.

    Reduce IBS project: multiple therapy choices and shared decision-making give IBS patients self-management and better quality of life

    Gastroenterology

    (2017)
  • F. Mearin et al.

    Bowel disorders

    Gastroenterology

    (2016)
  • K. Van den Houte et al.

    Prevalence and impact of self-reported irritable bowel symptoms in the general population

    United European Gastroenterol J

    (2018)
  • C. Canavan et al.

    Review article: the economic impact of the irritable bowel syndrome

    Aliment Pharmacol Ther

    (2014)
  • M. Corsetti et al.

    Novel pharmacological therapies for irritable bowel syndrome

    Expert Rev Gastroenterol Hepatol

    (2016)
  • M. Hawthorn et al.

    The actions of peppermint oil and menthol on calcium channel dependent processes in intestinal, neuronal and cardiac preparations

    Aliment Pharmacol Ther

    (1988)
  • D. Bautista et al.

    The menthol receptor TRPM8 is the principal detector of environmental cold

    Nature

    (2007)
  • Y. Karashima et al.

    Bimodal action of menthol on the transient receptor potential channel TRPA1

    J Neurosci

    (2007)
  • J. Walstab et al.

    Natural compounds boldine and menthol are antagonists of human 5-HT3 receptors: implications for treating gastrointestinal disorders

    Neurogastroenterol Motil

    (2014)
  • D. Trombetta et al.

    Mechanisms of antibacterial action of three monoterpenes

    Antimicrob Agents Chemother

    (2005)
  • S. Botschuijver et al.

    Reversal of visceral hypersensitivity in rat by Menthacarin®, a proprietary combination of essential oils from peppermint and caraway, coincides with mycobiome modulation

    Neurogastroenterol Motil

    (2018)
  • K. Rajkowska et al.

    Candida albicans impairments induced by peppermint and clove oils at sub-inhibitory concentrations

    Int J Mol Sci

    (2017)
  • B. Cash et al.

    A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms

    Dig Dis Sci

    (2016)
  • Cited by (75)

    • Peppermint essential oil

      2023, Essential Oils: Extraction, Characterization and Applications
    View all citing articles on Scopus

    Conflicts of interest These authors disclose the following: Ad A. M. Masclee and Daniel Keszthelyi have received a ZonMw (The Netherlands Organisation for Health Research and Development [Dutch government]), health care efficiency grant for the execution of this study. Ad A. M. Masclee and Daniel Keszthelyi have received an unrestricted research grant from Will Pharma SA, which also supported Zsa Zsa R. M. Weerts to attend a scientific meeting. Ad A. M. Masclee and Daniel Keszthelyi have received research funding from Allergan and Grünenthal (both unrelated to the current study). Ad A. M. Masclee has given scientific advice to Bayer and Kyowa Kirin and has received funding from PENTAX Europe GmbH. Daniel Keszthelyi has given scientific advice to Biocodex and Bayer. The employer of Daniel Keszthelyi and Ad A. M. Masclee has an agreement with Will Pharma SA regarding the exploitation of a potential market authorization of the ileocolonic formulation of peppermint oil for irritable bowel syndrome. Jacobus R. B. J. Brouwers has received a consultancy fee from Will Pharma SA. The employer of Henderik W. Frijlink has a license agreement with Will Pharma SA regarding the ColoPulse technology. Jan Tack has given scientific advice to Alfa Wassermann, Allergan, Christian Hansen, Danone, Grünenthal, Ironwood, Janssen, Kyowa Kirin, Menarini, Mylan, Neutec, Novartis, Noventure, Nutricia, Shionogi, Shire, Takeda, Theravance, Tramedico, Tsumura, Zealand, and Zeria Pharmaceutical and has served on the speakers bureau for Abbott, Allergan, AstraZeneca, Janssen, Kyowa Kirin, Menarini, Mylan, Novartis, Shire, Takeda, and Zeria. Annieke S. de Ruiter-van der Ploeg has received financial support from Allergan to attend a scientific meeting. The remaining authors disclose no conflicts.

    Funding Funding for this study was provided by a grant received from ZonMw (The Netherlands Organisation for Health Research and Development [Dutch government]), grant number 836031017. The study was initiated by the academic authors in collaboration with WillPharma SA, Wavre, Belgium. The independent ZonMw subsidizing committee, advised by external referees, had input in the study design. The peppermint oil capsules for this study have been provided in kind by Will Pharma SA, Wavre, Belgium. In addition, Will Pharma SA provided funding for the execution of the phase 1 study (Adv Ther 2018;35:1965–1978; https://doi.org/10.1007/s12325-018-0802-1), the execution of which was a prerequisite for receiving funding for the current study from ZonMw. The study design, data collection, analysis, and interpretation were done by the academic authors without industry involvement. The decision to submit was made by the academic authors with no restrictions imposed by the sponsor. WillPharma SA was provided the opportunity to review the manuscript before publication, but the content of the manuscript was at the sole discretion of the academic authors.

    Author names in bold designate shared co-first authorship.

    View full text