Effects of peppermint oil in patients with irritable bowel syndrome: a systematic review and meta-analysis

doi:10.21203/rs.3.rs-1896816/v1

Backgroud: The purpose of this meta-analysis was to investigate the clinical effects of peppermint oil (PO) on the treatment of irritable bowel syndrome（IBS).

Methods: Randomized controlled trials of PO for the treatment of irritable bowel syndrome were retrieved by computer from PubMed, Cochrane CENTRAL, EMBASE, and Web of science until December 30, 2021, and a meta-analysis was performed using Revman5.3 software.

Results: Seven high-quality studies included a total of 722 participants. PO improved both IBS Symptom Severity Scale (IBS-SSS) and IBS quality of life (IBS-QOL) scores, although not significantly better than placebo(IBS-SSS ：MD = 15.35, 95% CI: -25.16-55.86, P = 0.46;IBS-QOL：MD = 0.78, 95% CI: -0.18-1.74, P = 0.11)；IBS-Global improvement in symptoms (IBS-GIS）of the PO group improved significantly compared with the placebo group (RR = 1.62, 95% CI: 1.20-2.17, P = 0.002). The PO group had significantly higher adverse events than the placebo group (RR 1.48, 95% CI: 1.48-1.89, P = 0.0002).

Conclusions: While PO can significantly alleviate the clinical symptoms of IBS, the occurrence of adverse events will increase, and whether it will enhance IBS-SSS or IBS-QOL scores has to be researched further.

peppermint oil

irritable bowel syndrome

Randomized controlled trials

meta-analysis

According to the Roman IV, irritable bowel syndrome (IBS) is a gastrointestinal syndrome with chronic functional changes, mainly characterized by abdominal pain, bowel habit changes, and gastrointestinal dysfunction, and is classified in to four types: IBS with predominant diarrhea (IBS-D), IBS with predominant constipation (IBS-C), IBS with mixed bowel habit (IBS-M), and unclassified IBS (IBS-U)¹.IBS has a major impact on patients' physical health, quality of life, and economic status of patients, and its pathogenesis is extremely complicated. These include genetic and epigenetic factors, gut microbiota disorders and inflammation, increased abnormal colonic motility or transit, disruption of brain-gut mutual communication, altered gut physiology interactions, and psychosocial factors, among others². Muscle relaxants, antispasmodics, and dietary and lifestyle modifications can all help relieve symptoms in IBS patients, particularly abdominal discomfort and bloating³. Peppermint oil (PO) is a natural herbal supplement containing L-menthol that inhibits calcium channel receptors in the gastrointestinal tract while also having anti-inflammatory, antioxidant, immunomodulatory effects, etc., that allow for IBS-related treatments^4,5. There is numerous research now being conducted on the treatment of IBS using PO; however, its efficacy in the treatment of IBS is not completely consistent. As a result, the results of clinical trials with comprehensive data were meta-analyzed to evaluate the true efficacy of PO in the treatment of IBS.

1.1 Search Strategy

A systematic literature search was performed across the PubMed, EMBASE, and The Cochrane Library databases from inception until December 30, 2021 for articles on the research of PO in IBS patients. The search strategy was to follow the PRISMA principle， with the following key search terms: “Irritable Bowel Syndrome”, “IBS”， “Irritable Syndrome” “Peppermint oil”, “menthene”， “pennyroyal”， “MenthaPiperita”， “L-menthol”， “mint”， “Peppermint,” and “Menthahaplocalyx”. No restrictions were placed on date, language, or subject during the database search.

1.2 Inclusion and Exclusion Criteria

The following inclusion criteria were set: 1) randomized controlled trial study type; 2) study on the use of PO and placebo in the treatment of IBS, with the treatment period being >4 weeks; 3) adult subjects, in line with the diagnosis of IBS.

The following were the exclusion criteria: 1) not randomized controlled trials, such as cohort study or cross-sectional study; 2) treatment period being <4 weeks; 3) outcome indicators cannot be extracted.

1.3 Data extraction

The study titles and abstracts were independently read by 2 investigators and the data were extracted by the same authors. In case of a disagreement, the third investigator intervened. The contents of the data extraction included the name of the first author, year of publication, country, number of trial and control groups, follow-up time, and outcome indicators.

1.4 Study quality

The improved Jadad scale was used to evaluate the quality of the included studies. This scale includes 3 aspects: random sequence generation and randomized hiding, blinded method, and withdrawal or loss to follow-up. The scores were awarded as follows: 1-3 points = low quality and 4-7 = high quality.

1.5 Statistical analysis

Rev.man5.3 was used for data analysis, and the continuity variable was expressed as mean difference (MD). The results were tested for heterogeneity using the X2 test, which was measured in I². At P ＜ 0.05 or I²≥ 50%, statistical heterogeneity between the findings was indicated and analyzed using a random-effects model. At P ＞ 0.05 or I²＜ 50%, a fixed-effects model was employed. The data were converted according to the Cochrane manual for comparisons of pre- and post-treatment differences when comparing only the evaluation index before and after treatment x±s. P ＜ 0.05 indicated a statistically significant difference.

2.1 Literature retrieval and study characteristics

After removing duplicates from the original retrieval of 437 pieces of literature using an electronic database search, we discovered 184 studies. After reviewing the titles and abstracts, we eliminated 175 papers. Two were excluded: one was no-full-text research and the other was child research. Finally, a total of 7 high-quality studies with a cumulative sample size of 722 cases were considered, including 371 cases in the PO group and 351 cases in the placebo group. Figure 1 depicts the literature retrieval process, whereas Table 1 displays the fundamental information and quality evaluation of the included literature.

Table 1

Basic information and quality evaluation of the included literature IBS-SSS༚IBS-Symptom Severity Score VAS༚Visual Analogue Scale TISS༚Total IBS Symptom Score
Author	Year	Country	PO NO.	Placebo NO.	First outcome	Study Clycle	Jadad Scores
Nee,J	2021	USA	46	87	IBS-SSS	6 weeks	7
Weerts	2020	Netherlands	125	64	IBS-GIS	8 weeks	7
Mosaffa	2016	Iran	40	40	VAS	4 weeks	6
Cash	2016	USA	35	37	TISS	4 weeks	6
Merat	2010	Iran	45	45	The severity of abdominal pain	8 weeks	7
Cappello	2007	Italy	28	29	TISS	8 weeks	7
Liu	1997	China	52	49	alleviation of the severity of abdominal pain	4 weeks	6

2.2 IBS Symptom Severity Scale (IBS-SSS) Outcomes

The selected studies exhibited a high level of heterogeneity (I2 = 81%, P < 0.1) and were analyzed using random-effects models. Figure 2 depicts that a pooled analysis revealed that oral PO failed to significantly improve IBS-SSS scores in IBS patients when compared to the placebo group (MD = 15.35, 95% CI: -25.16-55.86, P = 0.46).

2.3 IBS Quality of Life (IBS-QOL) Outcomes

There was no heterogeneity between studies (I2 = 0%, P ༞ 0.1)and two studies that reported pre-treatment and post-treatment IBS-QOL (IBS quality of life score) values, which were analyzed using fixed-effects models. Figure 3 shows that a pooled analysis revealed that oral PO failed to significantly improve IBS-QOL scores in IBS patients when compared to the placebo group (MD = 0.78, 95% CI: -0.18-1.74, P = 0.11).

2.4IBS-Global improvement in symptoms(IBS-GIS)Outcomes

Four studies reported IBS-GIS improvement rates, no heterogeneity between the included studies (I2 = 0%, P༞0.1), analyzed using a fixed-effects model, and the results demonstrated that oral PO significantly relieved clinical symptoms in patients. Figure 4 depicts the results (RR = 1.62, 95%CI: 1.20–2.17, P = 0.002).

2.5 Adverse Outcomes

Six studies reported adverse of PO treatment, with no heterogeneity between studies (I2 = 33%, P༞0.1), using a fixed-effect model, which showed that oral PO increased the incidence of adverse reactions in patients compared to placebo (RR = 1.48, 95% CI: 1.48–1.89, P = 0.0002) (Fig. 5).

2.6 Sensitivity and bias

The included literature was excluded one by one in turn for the sensitivity analysis of more than two articles included, and the results showed that the exclusion of anyone literature would not significantly affect the pooled value of RR and its 95% CI. Simultaneously, the funnel plot of the two primary outcome indicators revealed that the included studies in this research were mostly above the funnel chart, and the left and right were fairly symmetrical, indicating that the publication bias was not obvious, as shown in Figs. 6 and 7.

There were studies on the treatment of IBS with PO as early as the 1980s, and since then, randomized controlled trials of PO for the treatment of IBS have increased. Since IBS is a disease with a diversity of clinical symptoms, the trial design and outcome are also variable. Two recent meta-analyses found that PO is safe and effective in the short-term treatment of IBS and can significantly improve clinical symptoms^{6, 7}. However, we found that the included studies' sample sizes were small and the quality of the research was uneven, so we re-searched the literature database to include additional high-quality studies and evaluate the effectiveness of PO in the treatment of IBS.

IBS is an exclusive disease with variable clinical symptoms that cannot be assessed by a single indicator, and it is more appropriate to judge the severity of the disease in the form of a scale of scores¹. Previous studies have shown a low FODMAP diet⁸, dietary fibre⁹, vitaminD¹⁰, and PO⁶ might ameliorate IBS symptoms. We included seven studies in this meta, Nee¹¹ and Weerts¹²covering IBS-SSS scores. They reached different conclusions, with the former showing that PO could reduce patients' IBS-SSS scores, but the difference was not statistically significant, and the latter showing that PO treatment significantly reduced patients' IBS-SSS scores, and the difference was statistically significant. According to the pooled analysis, PO treatment is ineffective in lowering the IBS-SSS score when compared to placebo (MD = 15.35, 95% CI: -25.16-55.86, P = 0.46). Both the studies were high-quality research articles that looked at the effects of a 6-week PO sustained treatment, whether the extended treatment has the same effects has to be confirmed by further studies. As far as we know, this is the first meta-analysis of IBS-SSS scores of PO, previous studies have focused on overall symptom relief rates or specific symptoms^{6, 7, 13}.

In addition, we analyzed another scale score (IBS-QOL), and the improvements in IBS-QOL scores obtained in this meta-analysis were not statistically significant (MD = 0.78, 95%CI: -0.18–1.74, P = 0.11). Similarly, vitamin D, although being a popular remedy for IBS, has not consistently demonstrated significant improvements in IBS-QOL scores¹⁴. Both Weerts¹² and Mosaffa¹⁵ studies showed that PO treatment was ineffective in improving patients' IBS-QOL scores relative to placebo. Different IBS scale scores are composed of different components, such as IBS-SSS, which consists primarily of five parts: abdominal pain discomfort, the number of days of mid-abdominal pain attacks every 10 days, the degree of bloating discomfort on the day, satisfaction with the stool situation, intestinal symptoms on life troubles, and the IBS-QOL which contains 34 parts. Each scale score has advantages and disadvantages; whether PO treatment may enhance IBS patients ‘scale scores or modify which scale score requires additional research to confirm. Previous studies have shown that PO can improve the clinical symptoms of IBS patients. This study included four randomized controlled trials ^{11, 12, 15, 16}, with a total of 364 subjects, assessing the overall improvement of symptoms (IBS-GIS) of PO treatment, and the pooled analysis showed that the clinical symptoms of patients after PO treatment improved significantly (RR = 1.62, 95% CI: 1.20–2.17, P = 0.002). Further sensitivity analysis of our meta-analysis results revealed that the outcome remained statistically significant, which was consistent with the previous meta-analysis of Khanna⁷, which showed that PO relieved symptoms by RR = 2.23 and 95% CI: 1.78 to 2.81 compared to placebo. The main mechanism of PO treatment of IBS and other dysfunctional diseases includes blocking of Ca2 + influx through sarcolemma L-type Ca2 + channels¹⁷ or directly affecting the enteric nervous system¹⁸ thereby, inhibiting the gastrointestinal smooth muscle contractility, or by transient receptor potential ion channel^{19, 20} to regulate visceral sensitivity, as well as having antibacterial, anti-inflammatory ^{21, 22} or anxiolytic^{23, 24} properties.

Of the six studies included in this study, four showed that the difference in adverse reactions between PO and placebo was not statistically significant^{16, 25–27}, but the other two showed that PO treatment was more likely to cause adverse reactions, and the difference was statistically significant^{1, 15}. This study’s pooled results showed that PO treatment was more prone to cause adverse reactions, with oral PO increasing the occurrence of adverse reactions in IBS patients (RR = 1.48, 95% CI: 1.48–1.89, P = 0.0002).

This study has the following limitations: 1. There are few studies on the IBS-SSS and IBS-QOL score scales for outcome indicators, whether increasing the number of studies or the sample size would result in changes in the results requiring additional research. 2. The definition of clinical symptom improvement varies per study. 3. The types and dosages of PO utilized in different studies varied, increasing the heterogeneity of the studies.

With the rise in the prevalence of IBS in recent years, there has been a growth in Pharmacotherapy for IBS, especially PO, as one of the potential therapeutic prospects. The results of this study suggest that consuming PO in the short term might alleviate clinical symptoms in IBS patients, but it can also cause some adverse reactions. More well-designed trial studies are needed to demonstrate PO’s efficacy and safety in IBS treatment.

PO：peppermint oil；IBS：irritable bowel syndrome；IBS-SSS：IBS Symptom Severity Scale ；IBS-QOL：IBS quality of life ；IBS-D：IBS with predominant diarrhea；IBS-C：IBS with predominant constipation；IBS-M：IBS with mixed bowel habit；IBS-U：unclassified IBS ；IBS-GIS：IBS-Global improvement in symptoms；MD ：mean difference ；RR：risk ratio；95%CI：95% confidence intervals；

Acknowledgements

Not applicable

Authors’ contributions

Ziqing Huang and Xiaomei Huang is equally contributed.

Ying Wan contributed to the study conception and design.Literature search was performed by Ziqing Huang and Xiaomei Huang Quality assessment and Data extraction and Statistical analysis was also performed by the two authors. The first draft of the manuscript was written by Ziqing Huang.The final version of the article was confirmed by Ying Wan

Funding

Not applicable

Availability of data and meterials

The data that support the findings of this study are available from PubMed, Cochrane CENTRAL, EMBASE, and Web of science

Ethics approval and consent to participate

Not applicable. This article does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable.

Competing interests

All authors declare no conflict of interest in this study.

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No competing interests reported.

Effects of peppermint oil in patients with irritable bowel syndrome: a systematic review and meta-analysis

Status:

Version 1

Abstract

Figures

Background

Methods

Results

2.2 IBS Symptom Severity Scale (IBS-SSS) Outcomes

2.3 IBS Quality of Life (IBS-QOL) Outcomes

2.4IBS-Global improvement in symptoms(IBS-GIS)Outcomes

2.5 Adverse Outcomes

2.6 Sensitivity and bias

Discussion

CONCLUSION

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1