Efficacy of Chinese Herbal Medicine for Diarrhea-Predominant Irritable Bowel Syndrome: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Trials

Objective. To explore the efficacy of Chinese herbal medicine in treating diarrhea-predominant irritable bowel syndrome (D-IBS). Methods. Four English and four Chinese databases were searched through November, 2015. Randomized, double-blind and placebo-controlled trials were selected. Data extraction and quality evaluation were performed by two authors independently. RevMan 5.2.0 software was applied to analyze the data of included trials. Results. A total of 14 trials involving 1551 patients were included. Meta-analysis demonstrated superior global symptom improvement (RR = 1.62; 95% CI 1.31, 2.00; P < 0.00001; number needed to treat = 3.6), abdominal pain improvement (RR = 1.95; 95% CI 1.61, 2.35; P < 0.00001), diarrhea improvement (RR = 1.87; 95% CI 1.60, 2.20; P < 0.00001), pain threshold assessment (MD = 54.53; 95% CI 38.76, 70.30; P < 0.00001), and lower IBS Symptom Severity Score (SMD = −1.01; 95% CI −1.72, −0.30; P = 0.005), when compared with placebo, while for defecation threshold assessment, quality of life, and adverse events, no differences were found between treatment groups and controlled groups. Conclusion. This meta-analysis shows that Chinese herbal medicine is an effective and safe treatment for D-IBS. However, due to the small sample size and high heterogeneity, further studies are required.


Introduction
Irritable bowel syndrome (IBS), the most common functional gastrointestinal disorder across the world, is characterized by recurrent abdominal pain or discomfort associated with disturbances in defecation and could not be explained by any structural or anatomical abnormality [1,2]. According to the different bowel behaviors, IBS could be divided into four subtypes, namely IBS-C (constipation-predominant), IBS-D (diarrhea-predominant), IBS-M (mixed), and IBS-U (unspecified) [2], among which IBS-D is the major subtype [3]. With the high prevalence of 14%∼28% among Europe [4] and 0.82%∼11.5% in China [5,6], it has serious influences on the quality of life of patients and costs a large amount of medical resources (1007.3 million in 2004), which is close to 25% of the total cost of all functional GI disorders (3988.8 million) [7].
Although with a great progress in the understanding of IBS [8], conventional treatments, including antidiarrheals, antispasmodics, antidepressants, probiotics and psychological treatments [9][10][11][12], were still limited in clinic because of side effects, costly medication expenses, and high relapse rates [13] and seemed to be unsuccessful to improve the quality of IBS patients' life [14]. Hence, an increasing number of patients (from 16% in 1986 to 51% in 2005) tend to use complementary and alternative medicine (CAM) [15]. Chinese herbal medicine (CHM), the major part of CAM and characterized by syndrome differentiation and treatment, has widely been accepted during last few decades [16]. Several clinical trials have been conducted, but the results were inconsistent [15,[17][18][19]. Although several systematic reviews have shown a therapeutic benefit, the efficacy of CHM was still controversial due to the poor qualities of the original studies, and these authors also emphasized that it was premature to recommend herbal medicines for routine use in IBS [20,21].
Recently, a high quality meta-analysis, which focused on soothing the liver and invigorating the spleen therapy, has demonstrated CHM is an effective treatment for IBS-D [22]. According to a literature review, spleen-stomach weakness (57.5%), yang deficiency of the spleen and kidney (52.5%), stagnation of liver qi, and deficiency of the spleen (52.5%) are the most common Traditional Chinese Medicine (TCM) syndromes in IBS-D [23]. In other words, soothing the liver, invigorating the spleen, and warming the kidney are the main therapies for IBS-D. Given all the information, a metaanalysis of randomized, double-blind, placebo-controlled trials is required to confirm whether CHM is beneficial to IBS-D patients.

Methods
The registered protocol of this systematic review could be found in the PROSPERO database (http://www.crd.york.ac .uk/PROSPERO/display record.asp?ID=CRD42015029540).

Search Strategy.
Two researchers searched four English electronic databases and four Chinese electronic databases from their establishments through November 2015, including PubMed, Web of Science, Cochrane Library, Embase, Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and WanFang Database. Conference proceedings and dissertations which involved unpublished trials were also searched from CNKI and WanFang databases.

Types of Studies.
Studies, performed as randomized, double-blind, placebo-controlled trials, which compared the efficacy and safety of CHM with placebo for IBS-D were included. English and Chinese were applied as language restriction.

Types of Participants.
Patients were diagnosed with IBS-D according to the ROME I, II, or III criteria.

Types of Interventions.
Orally administered CHM, in any preparations like capsules, decoctions, extracted granules, and oral liquids, were used alone in the treatment groups. The controlled groups only received placebos which were similar to the herbal medicines in taste, smell, and look. Treatment durations were not limited.

Types of Outcome
Measures. Primary outcomes were global syndrome improvement, IBS Symptom Severity Score (SSS). Secondary outcomes were abdominal pain improvement, diarrhea improvement, visceral hypersensitivity assessment, quality of life, and adverse events.

Study Selection and Data Extraction
According to the inclusion and exclusion criteria, study selection and data extraction were carried out by two researchers independently. The detailed information including diagnostic criteria for IBS-D, TCM syndrome, TCM therapy, population, baseline characteristics, details of the interventions, followup time, and outcome measurements were extracted to form a conclusive table. Any divergences were resolved by discussion and consensus with a third researcher.

Assessment of Risk Bias.
Using the Cochrane risk of bias tool, the methodological qualities of included trials were evaluated by two researchers, respectively [24]. The judgment of the other bias includes comparable baseline characteristic, for-profit, and inclusion and exclusion criteria into consideration. Disagreements were resolved through discussion and consensus with a third researcher.

Data
Analysis. RevMan 5.3 was the utilized software to analyze the data. We took dichotomous data as Relative  Risk (RR) and continuous variables as Mean Difference (MD) with 95% Confidence Intervals (CI). Standardized Mean Difference (SMD) analyses were performed when different measurement scales were used. Only the first phase outcome data were analyzed in cross-over trials. Both the Chi-squared ( 2 ) test and -squared ( 2 ) statistic were used for the assessment of heterogeneity [25]. If a significant heterogeneity existed ( 2 > 50% or < 0.05), a random effect model was performed to calculate the pooled RR. Otherwise, a fixed effect model was used [26]. In order to inquire into the origin of heterogeneity among studies, a sensitivity analysis was conducted by omitting one trial successively. The Number Needed to Treat (NNT) was calculated as the reciprocal of the therapeutic gain. Subgroup analysis for different TCM therapies was performed when the necessary data were available.

Study and Selection.
A total of 196 citations were identified for initial search and 15 articles, in which 2 articles [29,30] reported 1 trial, were involved at last (Figure 1).  the spleen (SLIS), warming the kidney and invigorating the spleen (WKIS), and individualized therapies were involved. Table 1 showed the detailed information of the included trials. The ingredients of herbal formulae were listed in Table 2.

IBS-QOL Score.
Three studies assessed the quality of life of the patients. Two [35,39]

Adverse Events.
Ten studies mentioned the adverse events and 5 [33,[35][36][37][38] reported no adverse event occurred. Bensoussan et al. [27] reported 2 patients withdrew due to upper gastrointestinal discomfort and headaches, respectively, in standard treatment group. Wang et al. [31] reported 1 flush and abdominal pain case. Leung et al. [18] reported 2 patients had skin rash and thyroiditis in TCM group and 1 had facial nerve palsy in placebo group. In Chen et al. 's study [34], 2 mild nausea and mild pruritus cases were noted. And 2 cases of headache, 1 case of low-back pain, and 1 case of dysmenorrhea were reported by Ko et al. [39]. No difference of adverse events was observed between CHM and placebo. In subgroup analysis SLIS, WKIS and individualized groups' therapeutic gains over placebo were 18.3%, 46.2%, and 18.8%, and the NNT were 5.5, 2.2, and 5.6, respectively. That being said, WKIS seemed to be the best therapy for IBS-D. But as we all know, syndrome differentiation and treatment are the core of TCM. The efficacy of TCM derives from the accuracy of syndrome differentiation [23]. In Bensoussan et al. 's [27] study, no significant difference was noticed between the standard group and individualized group at the end of the 8-week procedure. But the individualized group maintained a better improvement after a 14-week followup. Therefore, using TCM syndrome differentiation is still required to enhance the pertinence of treatment.

Discussion
Anorectal manometry was used to assess the visceral hypersensitivity. CHM could significantly increase the pain threshold. That meant CHM could reduce visceral pain. While meta-analysis did not show an advantage in defecation threshold between CHM and placebo, both of the two studies showed that the CHM groups had significant improvements while placebo groups had not. In Shen et al. 's [30] study, the initial defecation threshold in CHM group (79.29±34.11 mL) was lower than the placebo group (87.00 ± 21.00 mL).   Heterogeneity: 2 = 1.00, df = 2 (P = 0.61); I 2 = 0% Test for overall effect: Z = 6.92 (P < 0.00001)      In Li's study, the disease durations were shorter than the other four studies [29,33,35,38]. This may contribute to the heterogeneity mostly. In addition, the different TCM syndromes and therapies also could be a matter of heterogeneity.

Interpretation.
With the deepening of the research, an increasing number of mechanisms of CHM in treating IBS-D were revealed. The effective targets included the regulation of hormones and cytokines in the enteric nervous system, the adjustment of the brain-gut axis, and the modulation of the gut motility [41]. Besides, in Ko et al. 's [39] study, Huo Xiang Zheng Qi San (a CHM formula) showed a tendency to have a lower Firmicutes/Bacteroidetes ratio and intestinal permeability index, which could relieve the IBS symptoms. Increased expressions of CD45+ and CD3+ and a decreased CD4+/CD8+ ratio, meaning an immunity disorder, were found in IBS rats, while CHM, which acted to warming the kidney and invigorating the spleen, could reduce the expressions of CD45+ and CD3+ and increase the CD4+/CD8+ ratio, indicating a regulative effect in immune response [42].
Cheng [32] and Shen et al. [30] studies both showed an improvement in visceral hypersensitivity, which was caused by a variety of factors and was believed to have a large contribution to the genesis of IBS [43]. This result may through the reduction of serotonin (5-HT) both in serum and enteric mucosa [32] lead to a relief of visceral pain [30].

Strengths and Limitations.
Several strengths were contained in this meta-analysis. First, this is a systematic review on a significant issue of human health. Second, the inclusion and exclusion criteria were strict and the methodological quality of the included trials was commonly rated as high after a rigorously assessment. Furthermore, a standard protocol of this meta-analysis was registered and published in PROSPERO database. However, this meta-analysis still had some limitations. First, because of the strict inclusion criteria, the suitable trials were few and the sample sizes were small. Second, 12 out of 14 trials were carried out in China and 10 studies were printed in Chinese. A funnel plot analysis was not performed successfully due to inadequate number of included studies in meta-analysis, so potential publication bias may exist. Third, owing to insufficient suitable literatures, this meta-analysis did not involve other TCM syndromes such as cold-heat in complexity and spleen-stomach weakness. Fourth, the course of treatment, ranging from 3 to 16 weeks, as well as the follow-up duration, from 2 to 14 weeks, was not long enough to appraise the efficacy and safety of CHM.

Implications for Further Study.
Although all the studies were generally well designed, several issues still should be addressed to improve the methodological quality of the clinical studies. First, a sample size calculation should be performed before enrollment. Second, randomization, allocation concealment, and blinding methods should be described expressly and reported fully in the article. Third, withdrawal/dropout during the study and use of ITT analysis should be reported clearly. Fourth, due to the relapsed nature of IBS, a sufficient followup duration is required to evaluate the long-term efficacy. Fifth, a link of a registered protocol is required in the article.

Conclusion
From the above, this meta-analysis demonstrates that SLIS and WKIS are feasible, effective, and safe treatments superior to placebo in improving global symptoms, IBS-SSS, abdominal pain, diarrhea, and visceral hypersensitivity with IBS-D. However, due to the small sample size and the high heterogeneity, a confirmative conclusion is still premature. In future studies, larger sample sizes and longer courses should be undertaken to perfect the studies.