By Joshua Coutinho, MD, and Nancy Selfridge, MD
Dr. Coutinho is a Clinical Skills Facilitator, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies
Dr. Selfridge is Professor, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies
Dr. Coutinho and Dr. Selfridge report no financial relationships relevant to this field of study.
SYNOPSIS: The PERSUADE study, a randomized, placebo-controlled trial of two formulations of peppermint oil, demonstrated no statistically significant reduction in abdominal pain response nor overall symptom relief in Rome IV IBS patients using Food and Drug Administration/European Medicines Agency endpoint criteria over an eight-week trial period.
SOURCE: Weerts ZZRM, et al. Efficacy and safety of peppermint oil in a randomized double-blind trial of patients with irritable bowel syndrome. Gastroenterology 2019; S0016-5085(19)41246-8. doi:10.1053/j.gastro.2019.08.026. [Epub ahead of print].
EXECUTIVE SUMMARY
- Two peppermint oil formulations (a small intestinal-release product and an ileocolonic-release product) did not reduce abdominal pain response nor provide overall symptom relief compared to placebo.
- Small intestinal-release peppermint oil did significantly reduce abdominal pain, discomfort, and irritable bowel syndrome severity as secondary outcomes; ileocolonic-release peppermint oil demonstrated no significant symptom reduction.
- Adverse events related to peppermint oil were mild and transient, consisting mainly of heartburn and gastroesophageal reflux-type symptoms.
Irritable bowel syndrome (IBS), a high-prevalence (10-20%), complex, gut-brain functional disorder, is associated with a significant negative effect on patients’ quality of life. Current pharmaceuticals include antispasmodics, laxatives, antidiarrheal agents, and antidepressants. None of these demonstrate high-level effectiveness for all symptoms and several have significant side effects, risks, or drawbacks, including cost.1
Historically, peppermint oil has been used in herbal pharmacopeia for treating digestive disorders, including dyspepsia and gallbladder disease. Meta-analyses of peppermint oil research have concluded that moderate evidence exists for the use of peppermint oil for IBS-related abdominal pain.2 In fact, the Canadian Gastroenterology Association clinical practice algorithm for IBS treatment includes soluble fiber and peppermint oil as initial treatments for IBS defecation-related abdominal pain, before considering prescription medication.3 Active ingredients in peppermint include menthol and other volatile oils that appear to relax smooth muscles through the antagonism of calcium channels in the gut.2 The introduction of Rome IV Criteria for IBS diagnosis, as well as changes in Food and Drug Administration (FDA) and European Medicines Agency (EMA) defined IBS trial endpoints focused on reduction of IBS-associated abdominal pain, prompted the authors of this study to a re-evaluate the efficacy and safety of peppermint oil within these strict outcome parameters.4,5
The PERSUADE trial is a randomized, double-blind, placebo-controlled study, conducted in four secondary and tertiary hospital care centers in the Netherlands that evaluated peppermint oil for the management of IBS as defined by Rome IV criteria. (See Table 1.) The trial recruited 189 patients between the ages of 18 and 75 via primary care and hospital outpatient clinics, as well as self-referral through public advertising and social media. Eligible patients were those who met Rome IV criteria and averaged numerical rating scale (NRS) pain scores of at least three on an 11-point scale of 0-10 with “0” representing “no pain” and “10” representing “worst pain ever,” over the course of a 14-day pretreatment period. Patients were randomized, using ALEA Screening and Enrollment Application Software, with respect to IBS type (constipation, diarrhea, or mixed), study center, age, and gender. Patients were placed within one of three treatment groups: small intestine-release peppermint oil, ileocolonic-release peppermint oil, and placebo. Treatment consisted of one self-administered capsule, containing 182 mg (0.2 mL) of peppermint oil, three times daily, 30 minutes before breakfast, lunch, and dinner over the course of eight weeks. All capsules were coated with an additional hard encapsulation of gelatin to ensure no peppermint scent or flavor interfered with blinding. Primary and secondary endpoints were measured weekly using NRS scales for pain and global symptom relief, as well as several other symptom and quality of life surveys, and results were recorded via electronic data capture.
Table 1. Rome IV Diagnostic Criteria for Irritable Bowel Syndrome |
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The primary endpoint for determining efficacy of peppermint oil was strictly defined (according to the FDA) as a reduction in weekly average abdominal pain compared to baseline by at least 30% in at least 50% of the treatment period using the NRS 11-point pain survey, which was assessed daily. The co-primary endpoint, per EMA recommendations, was global relief of IBS symptoms on an NRS seven-point survey, in at least 50% of the weeks during the eight-week treatment period, assessed weekly.
Secondary endpoints defined efficacy of peppermint oil by less strict outcomes on the NRS 11- and seven-point instruments, and included a variety of online surveys assessing reduction in IBS symptom severity, symptomatic improvement of abdominal pain, abdominal discomfort, abdominal bloating, abdominal cramping, belching, nausea, defecation urgency, anxiety, and quality of life. Incidence, nature, and severity of adverse effects occurring during the treatment period were documented daily.
Sample sizes were estimated using data from a 2014 Journal of Clinical Gastroenterology meta-analysis adjusted for heterogeneity and the anticipated dropout rate.6 All analyses were subject to the intention-to-treat principle. Per-protocol analyses were performed for data sets from patients who demonstrated 80% adherence to treatment and completed the treatment period. Because of multiple between-group comparisons, two-sided P values ≤ 0.04/5 = 0.0125 were considered statistically significant for the primary outcomes. Secondary outcomes with α < 0.025 were determined statistically significant.
There was no statistically significant difference in the reduction in the weekly average abdominal pain primary endpoint between peppermint oil treatment groups vs. placebo: 46.8% in small intestinal-release peppermint oil (odds ratio [OR] 1.68; 95% confidence interval
[CI] [0.80, 3.51]; P = 0.170; number needed to treat [NNT] 8.1) and 41.3% in ileocolonic-release peppermint oil (OR 1.39; 95% CI [0.66, 2.90]; P = 0.385; NNT 14.5), compared with 34.4% in placebo. (See Table 2.) There was no statistically significant difference in the co-primary outcome of global relief of IBS symptoms between treatment groups and placebo: 9.7% in small intestinal-release peppermint oil (OR 2.12; 95% CI [0.49, 9.17]; P = 0.317), and 1.6% in ileocolonic-release peppermint oil (OR 0.33; 95% CI [0.03, 3.35]; P = 0.351), compared with 4.7% in placebo. (See Table 2.)
Table 2. Peppermint Oil Effect on Irritable Bowel Syndrome Symptoms |
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|
Placebo |
Small Intestinal-Release Peppermint Oil |
Ileocolonic-Release Peppermint Oil |
|
|
# Responders (%) |
# Responders (%); P value; Odds Ratio (95% CI) |
# Responders (%); P value; Odds Ratio (95% CI) |
|
|
Primary Endpoints |
|||
|
Abdominal Pain, 30%* |
22 (34.4) |
29 (46.8); P = 0.170; 1.68 (0.80-3.51) |
26 (41.3); P = 0.385; 1.39 (0.66-2.90) |
|
Global relief** |
3 (4.7) |
6 (9.7); P = 0.317; 2.12 (0.49-9.17) |
1 (1.6); P = 0.351; 0.33 (0.03-3.35) |
|
Secondary Endpoints |
|||
|
Moderate relief† |
13 (20.3) |
24 (38.7); P = 0.030; 2.47 (1.09-5.56) |
13 (20.6); P = 0.980; 0.99 (0.41-2.38) |
|
Abdominal Pain, 50%†† |
8 (12.5) |
16 (25.8); P = 0.062; 2.51 (0.96-6.59) |
13 (20.6); P = 0.220; 1.85 (0.69-4.96) |
|
*At least 30% reduction in mean worst abdominal pain in at least 4 out of 8 weeks (Food and Drug Administration recommendation) **A global relief score of at least 6 or 7 (on a 7-point NRS) in at least 4 out of 8 weeks (European Medicines Agency recommendation) †A global relief score of at least 5, 6, or 7 (on a 7-point NRS) in at least 4 out of 8 weeks ††At least 50% decrease in mean worst daily abdominal pain in at least 4 out of 8 weeks CI: confidence interval |
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Noteworthy findings outside the strictly defined primary and co-primary endpoints were reported. During week 8, for example, patients receiving small intestinal-release peppermint oil had a significantly greater reduction in abdominal pain, with a corrected difference in change from baseline on the 11-point NRS, compared with placebo, of -0.63 (95% CI [-1.14, -0.12]; P = 0.016). Patients receiving small intestinal-release peppermint oil also experienced reduction in the secondary outcome of abdominal discomfort. Corrected differences in change from baseline on the 11-point NRS were significant during week 6 (-0.95; 95% CI [-1.74, -0.15]; P = 0.020) and week 7 (-0.97; 95% CI [-1.71, -0.24]; P = 0.009) of treatment. The secondary outcome of IBS symptom severity was improved in patients receiving small intestinal-release peppermint oil, with a corrected difference in change from baseline of 41.8 on the IBS Symptom Severity Score total score. An improvement of -91.5 for small intestinal-release peppermint vs. -49.8 for placebo was seen during week 8 of treatment (95% CI for difference [-76.88, -6.70]; P = 0.020).
Adverse effects, such as heartburn, belching, and headache, were more prevalent in both groups of patients receiving peppermint oil. Reported mean for side effects was 4.26 (0.37) for small intestinal-release (P = 0.012) and 4.54 (0.45) for ileocolonic-release peppermint oil (P = 0.001) compared with 2.78 (0.34) for placebo.
COMMENTARY
This is the first high-quality randomized, double-blinded, placebo-controlled investigation of peppermint oil for relieving IBS symptoms. This accomplishment alone is commendable. Although this IBS interventional study concludes that peppermint oil does not improve IBS pain and global symptoms, it does so using the FDA and EMA outcome endpoints for the NRS 11 and NRS 7 instruments, respectively. The authors admit that these stringent outcome endpoints may not reasonably reflect clinical response given the wide range of symptoms commonly suffered by IBS patients and the perceived impact on quality of life. In fact, pain and global symptom improvement with small intestinal-release peppermint oil did reach statistical significance in this study, when lower NRS 11 and NRS 7 thresholds were used and additional secondary outcome measures of symptom improvement and quality of life were applied. These latter findings are consistent with the results of recent meta-analyses indicating a beneficial effect of peppermint oil for IBS symptoms.6-8 Further, adverse events related to both peppermint oil formulations were mild and transient, and consisted mostly of self-limited heartburn and gastroesophageal reflux disease symptoms, likely related to the proven relaxing effects of the menthol component of the oil in the lower esophageal sphincter. When compared to placebo-controlled studies evaluating several newer IBS drugs (linaclotide, plecanatide, eluxadoline), small intestinal-release peppermint oil performed similarly in this study in terms of NNT. All pharmaceutical agents currently marketed to treat IBS have significantly less favorable adverse event profiles. Peppermint oil is inexpensive compared to pharmaceuticals, as well. A 30-day supply (enough for three doses per day) of 0.2 mL enteric coated peppermint oil capsules can be purchased from a popular online marketplace vendor for approximately $12.
One aim of the authors of this study was to evaluate an ileocolonic-release peppermint oil formulation, based upon the hypothesis that a more local anti-nociceptive effect on colonic sensory afferent receptors would demonstrate superior effectiveness. This was not the case and the authors concluded that further pursuit of this novel formulation as an IBS intervention is not indicated.
Because of the low cost, mild and transient side effect profile, and demonstrated moderate efficacy for IBS symptoms supported by this well-constructed study, peppermint oil remains an appropriate treatment in initial IBS defecation-related abdominal pain symptom management for patients who prefer a non-pharmaceutical, plant-based option.
REFERENCES
- Ford AC, et al. Irritable bowel syndrome. N Engl J Med 2017; 376:2566-2578.
- Kligler B, Chaudhary S. Peppermint oil. Am Fam Physician 2007; 75:1027-1030.
- Moayeddi P, Andrews CN, MacQueen G, et al. Canadian association of gastroenterology clinical practice guideline for the management of irritable bowel syndrome (IBS). J Can Assoc Gastroenterol 2019;2:6-29.
- U.S. Department of Health and Human Services Food and Drug Administration. Guidance for Industry – Irritable Bowel Syndrome Clinical Evaluation of Drugs for Treatment. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/irritable-bowel-syndrome-clinical-evaluation-products-treatment. Accessed Oct. 25, 2019.
- European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on the evaluation of medicinal products for the treatment of irritable bowel syndrome. Available at: https://www.ema.europa.eu/en/evaluation-medicinal-products-treatment-irritable-bowel-syndrome. Accessed Oct. 25, 2019.
- Khanna R, MacDonald JK, Levesque BG. Peppermint oil for the treatment of irritable bowel syndrome: A systematic review and meta-analysis. J Clin Gastroenterol 2014;48:505-512.
- Ruepert L, Quartero AO, de Wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2011;CD003460.
- Alammar N, Wang L, Saberi B, et al. The impact of peppermint oil on the irritable bowel syndrome: A meta-analysis of the pooled clinical data. BMC Complement Altern Med 2019;19:21.
The PERSUADE study, a randomized, placebo-controlled trial of two formulations of peppermint oil, demonstrated no statistically significant reduction in abdominal pain response nor overall symptom relief in Rome IV IBS patients using Food and Drug Administration/European Medicines Agency endpoint criteria over an eight-week trial period.
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