Background
The irritable bowel syndrome (IBS) is a chronic, functional gastrointestinal syndrome characterized by relapsing abdominal pain and altered bowel habits, with either predominant symptoms of diarrhea (IBS-D), constipation (IBS-C), both (IBS-M), or undetermined (IBS-U), and is categorized according to the Rome IV criteria [
1]. As a common digestive tract disorder, IBS affects an estimated 5–15% of Western populations [
2]. Lovell and Ford conducted a meta-analysis of the world’s literature and reported that, on a global scale, IBS is seen predominantly in females, and the age of onset is typically under 50 years-of-age [
3]. In their research, Lovell and Ford found the global prevalence of IBS to be 11.2% (95% confidence interval [CI], 9.8–12.8%) [
3]. IBS accounts for a significant number of annual visits to primary care physicians, health-care utilization, quality of life, and adverse economics owing to absenteeism from work [
4].
The pathophysiology of IBS is complex and involves an interaction of various factors, which includes, but is not limited to, genetic predisposition, gut-brain axis, visceral sensitivity, gastrointestinal motility, gut dysbiosis, neurotransmitters, food reactions, intestinal permeability, bile acids, inflammatory mediators, early-life stressors, psychosocial maladaptation, and somatization, among others [
5]. IBS patients with mild and intermittent symptoms usually benefit from lifestyle and dietary modification, which includes a diet low in fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) [
6]; and in some cases, lactose and gluten avoidance [
7]. Smooth muscle relaxants and antispasmodics can also be used to help with IBS symptoms, especially abdominal pain and bloating [
8].
Peppermint oil (PO) (
Mentha Piperita) is a naturally-occurring carminative herb containing monoterpene compounds that target the pathophysiology of IBS. PO contains L-menthol, which blocks calcium channels in smooth muscle, thus producing antispasmodic effects on the gastrointestinal tract [
9]. PO possesses antimicrobial, anti-inflammatory, antioxidant, immunomodulating, and anesthetic activities, all of which may be relevant for the treatment of IBS [
10‐
12]. Several case reports, observational studies, and randomized clinical trials (RCTs) with methodological inconsistencies and heterogeneous outcomes have been reported since the research conducted by Rees et al. in 1979 [
8,
13‐
20]. Earlier systematic reviews of RCTs of PO for IBS treatment revealed trial design flaws (e.g., no washout period for crossover trials), short follow-up duration, and conflicting trial results [
14,
21]. Some more recent systematic reviews of RCTs of PO for IBS treatment were limited in the lack of evidence for adverse events [
8,
18]. In addition, the risk-benefit profile of PO has been evolving as new RCTs continue to arise.
In 2016, Cash et al. reported the findings of a 4-week double blinded, placebo controlled RCT which tested a novel, proprietary, enteric-coated peppermint formulation (IBgard®) for its potential efficacy in reducing IBS symptoms in 72 patients with IBS-M or IBS-D [
22]. The specialized enteric-coating utilized in their trial consisted of a solid-state matrix that was triple-coated and designed to deliver PO with sustained release to the small intestine with fewer potential adverse effects. After 24 h. of treatment, there was a reduction in the total IBS symptom score over baseline (mean change − 0.55, SD ± 0.613) vs. placebo (mean change − 0.27, SD ± 0.342) (
p = 0.0092). At trial completion, there was a 40% reduction in the total IBS symptom score in the PO group compared to baseline (mean change − 1.16, SD ± 0.807) vs. 24.3% (mean change − 0.70, SD ± 0.737) with placebo (
P = 0.0246). There was an increased improvement in both multiple and individual gastrointestinal symptoms, as well as in severe or unbearable symptoms compared to the placebo.
Given the recent findings by Cash et al. [
22] and the potential limitations of previous meta-analyses, we conducted a systematic review and meta-analysis of available RCTs to determine the effect of peppermint oil in reducing the abdominal pain and global symptoms of irritable bowel syndrome and to evaluate the possible side effects of PO as compared to the placebo.
Discussion
In this systematic review, we assessed the largest cohort of RCTs published over five decades involving twelve randomized clinical trials with 835 IBS patients from around the world. Overall, treatment with PO significantly improves abdominal pain and global symptoms of IBS. The available data are also consistent with a good safety profile. The strength of our findings is reflected by the large effect size of PO over placebo in the improvement of abdominal pain and global symptoms and by the low heterogeneity across included studies.
The first systematic review of RCTs of PO for the treatment of IBS was published by Pitter and Ernst in 1998, which included eight randomized trials involving 295 patients with seven of the eight trials not using the accepted clinical features of IBS [
14]. The researchers performed a quantitative synthesis of five double-blind, placebo-controlled RCTs involving 265 participants [
20,
33,
34,
38,
40]. Four of the five RCTs had a Jadad methodological quality score of three, with no RCTs scoring the maximum of five points [
41]. Overall, the results demonstrated that PO was effective for the improvement of global symptoms in IBS (
p < 0.001). However, two of the five studies showed no difference when using a placebo in IBS symptom improvement, and overall, there was a significant variation between the placebo responses across the five studies (13–52%,
p < 0.01). No definitive conclusion could be drawn owing to the low quality of the primary studies, the overrepresentation of short-term (< 1 month duration) studies, and the use of cross-over designs without washout periods in four of the five RCTs. The authors acknowledged that the results of their meta-analysis needed to be interpreted with caution due to the mentioned methodological flaws in the included studies. We also observed that six of the eight trials included in the Pittler and Ernst review [
14] had treatment periods of one month or less. The studies included in this meta-analysis had treatment periods of two to twelve weeks, with seven studies being four weeks or greater, and found a significant benefit for PO relative to placebo for the improvement of abdominal pain and global IBS symptoms.
In 2004, Lesbros-Pantoflickova et al. performed a meta-analysis of the available pharmacological treatments for the irritable bowel syndrome, which included PO [
21]. The authors included five studies [
20,
33,
34,
38,
40], with four having a Jadad score ≥ 3 [
33,
38,
40]. Overall, the odds ratio (OR) of the five included studies favored PO for global symptoms over the placebo [OR 3.6, 95 CI% 2.2–6.0]. Lesbros-Pantoflickova et al.’s systematic review and meta-analysis lacked several methodological details and improperly concluded that Pittler’s meta-analysis failed to demonstrate a beneficial effect for PO vs. placebo for improving IBS symptoms [
14].
In 2008, Ford et al. reported the results of a qualitative and quantitative synthesis of the available studies for the effect of fiber, antispasmodics, and PO in the treatment of IBS [
8]. Four of the included studies had a Jadad score ≥ 3 [
30,
31,
34,
35] with a total of 392 participants to evaluate the effect of PO versus placebo on IBS symptoms. Ford et al. excluded the cross-over trials included by Pittler and Ernst [
14]. They reported that the relative risk of persistent symptoms was 43% less with PO (52/197; 26%) when compared to placebo (127/195; 65%) (relative risk, 0.43) without any significant heterogeneity between studies (
I2 = 31.1%,
P = 0.23). The number needed to treat (NNT) with peppermint oil to prevent one patient from having persistent symptoms was 2.5 (2.0–3.0). The methodological details of the selection criteria and extraction were provided, however, the criteria to define symptom improvement was heterogeneous and included pain and/or global symptom improvement [
8]. We separately analyzed the ability of PO to improve abdominal pain and global IBS symptoms. A limited risk of bias showed that all studies lacked concealed allocation. It is worth mentioning that a meta-analysis was not conducted on the side-effect data as only three trials reported adverse events.
In 2011, Ruepert et al. published the results of their systematic review and meta-analysis on the effectiveness of antispasmodics, antidepressants, and bulking agents in IBS, which included the randomized controlled trials of PO versus placebo [
17]. PO was shown to improve global symptoms; risk ratio was 2.25 [1.70–2.98] in two studies with 225 patients [
31,
34]. PO also improved the IBS symptom score vs. placebo; risk ratio was 1.94 [1.09–3.46] in three studies with 269 patients [
30,
31,
42]. Their analysis of spasmolytics for the relief of abdominal pain demonstrated the superiority of PO versus placebo; risk ratio was 2.15 [1.54, 3.00] in one trial of 101 patients [
35].
The most recent meta-analysis by Khanna et al. (2014) evaluated 726 patients [
19] from nine [
29,
30‐
32,
34‐
37,
43] included studies. Global IBS symptom improvement was reported to be greater for PO versus placebo (5 studies, 392 patients, relative risk 2.23; 95% confidence interval, 1.78–2.81), and likewise for improvement in abdominal pain (5 studies, 357 patients, relative risk 2.14; 95% confidence interval, 1.64–2.79). Khanna et al.’s pooled analysis of seven studies and 474 patients reported that IBS patients treated with PO, as compared to the placebo, were more likely to experience an adverse event, such as heartburn, which tended to be mild and transient [
19].
In 2018 Ford et al. published a systematic review of RCTs using medical, psychological and nutritional therapies for IBS as an updated monograph for the American College of Gastroenterology [
44]. The 2014 version included five RCTs of PO versus placebo for IBS [
45]. The primary outcome of improved IBS outcome was not defined according to global symptoms versus pain relief. The search terms were merged for a number of interventions (i.e. fiber, diet) with colpermin and peppermint oil being utilized to identify RCTs using PO for IBS. Seven RCTs involving 634 patients were included and the pooled analysis showed benefit for PO over placebo (RR-0.54; 95% CI 0.39–0.76). The number needed to treat in order for one patient to benefit was four but the endpoint of IBS improvement was not defined and heterogeneity was high (
I2 = 73%,
P = 0.001). Pooled data on adverse events from six studies did not show a difference between PO and placebo. One of the two new included studies was a comparative study of peppermint oil and anise oil to placebo [
46] with a visual analog scale and quality of life as primary and secondary endpoints. For these reasons, this study was excluded from our analysis.
Overall, we evaluated 835 adult patients from twelve studies that met the inclusion criteria. Improved global IBS symptomatology was greater for PO when compared to placebo, as well as for abdominal pain. We included studies excluded by Khanna et al. [
20,
22,
33,
38] and excluded their included study on pediatric IBS [
47]. Unlike Khanna et al., we did not detect a difference in the adverse events reported in IBS subjects using PO versus placebo. Our risk of bias analysis also differed from that of Khanna et al., as we found a high risk of bias for Cash et al. [
22] for industry funding and attrition bias for Cappello et al. [
30], Rees et al. [
20], and Weiss et al. [
37], which shall bring necessary caution to result interpretation. In our study, the number needed to treat with PO to prevent one patient from having persistent symptoms was three for global symptoms and four for abdominal pain.