Tong-xie-ning, a Chinese herbal formula, in treatment of diarrhea-predominant irritable bowel syndrome: a prospective, randomized, double-blind, placebo-controlled trial

Abstract

Currently the main components of treatment for irritable bowel syndrome (IBS) include patient education and reassurance, dietary modification, symptomatic treatment, and psychological treatment, but little evidence exists that the current pharmaceutical agents routinely used in treating IBS patients are efficacious.1 Partly from lack of effective conventional therapeutics and in search of better treatment options, many patients with IBS in both the east and west have turned to complementary and alternative approaches, including traditional Chinese medicine (TCM).2,3 TCM represents one aspect of Chinese medical philosophy that is characterized by its emphasis on maintaining and restoring balance. This medical approach is much more appropriate to disease prevention and the treatment of chronic disease including IBS.4 Though herbal medications have been used in many countries for the treatment of patients with IBS, randomized controlled trials’ (RCTs) data supporting the efficacy of these treatments in patients with IBS are still lacking.1 Tong-xie-ning granule (TXNG), a Chinese herbal formula, was used widely based on clinical experience rather than the evidence of RCTs in the treatment of diarrhea-predominant IBS. In this study, a rigorous RCT was undertaken to evaluate its safety and efficacy. METHODS Study design and setting This prospective, randomized, placebo-controlled, double-blind clinical trial was conducted in West China Hospital at Sichuan University. Patients and ethics All patients with diarrhea-predominant IBS (n=60) were recruited from the outpatient department in West China Hospital from March to December 2004, if they met both the Rome II criteria5 and the syndrome criteria of stagnation of the liver (Gan) Qi attacking the spleen in TCM.6 The inclusion criteria were: a diagnosis with diarrhea-predominant IBS ruling out an organic cause by screening of ultrasound, colonoscopy and stool examination, the syndrome criteria of stagnation of the liver Qi attacking the spleen in TCM, age 18 to 65 years and written informed consent. The exclusion criteria were: constipation-predominant IBS, IBS medication during the run-in period and/or study period, allergies to food additives, drugs and any components in TXNG, inflammatory bowel disease, current alcoholism or drug abuse, current psychiatric illness or dementia, pregnancy or breast-feeding, participation in any other studies during the past 6 months, serious disease of the heart, lung, kidneys, liver, central nervous system or haematopoietic system, cancer or the inability to understand this study. All eligible subjects were randomized into the TXNG group or the placebo group. The randomization list for this double-blinded, randomized study was computerized by the PRCO PLAN of the analysis system of SAS (Version 6.12 for Windows). The details of the allocation sequence were in a sealed envelope and unknown to the study investigators and the participants with IBS. Randomization was designed so that each participant would have a 50% chance of assignment to either the TXNG group or the placebo group. The Medical Ethics Committee of West China Hospital at Sichuan University approved this study and it is in accordance with the recent principles of the Declaration of Helsinki.7 All patients gave informed consent. Patients were free to withdraw from the study at any time. Interventions After initial gastroenterological screening, all included patients with diarrhea-predominant IBS entered a 2-week run-in period, the goal of which was to wash out any IBS medication that had been used previously. Thereafter all randomized patients were to receive either TXNG or placebo while all study personnel and patients were blinded to treatment assignment throughout the course of the study. TXNG was supplied by Chongqing Huasen Pharmaceutical Company (Chongqing, China) and its composition is presented in Table 1. The TXNG contained 5.0 g of an aqueous, spray-dried extract of the four herbs, which included at least 20 mg of paeoniflorin in guaranteeing the quality standardization. The placebo granule was indistinguishable from the TXNG in form, color, taste, size and packaging. The subjects in the TXNG group received 5.0 g of TXNG 3 times daily for 3 weeks, whereas the patients in the placebo group received 5.0 g of placebo 3 times daily for 3 weeks. All patients were treated in an equivalent fashion. Compliance was assessed by the granule count. In addition, no special instructions were given to patients regarding diet8 for avoiding foods known to cause them gastrointestinal tract irritation.Table 1: Standard formula of Tong-Xie-Ning granuleOutcome measures Patients completed the questionnaires before randomization at baseline and after 1 week and 3 weeks. The IBS-related “effects of pain on daily life” were assessed using a visual analogue of numeric pain intensity scale (NPIS; 1 to 10), which was subdivided into categories “non-existent” (0 score), “mild” (1 to 3 score), “moderate” (4 to 6 score), and “severe” (7 to 10 score). The IBS-related pain condition including the degree, the frequency and the duration per week and the IBS-related stool condition, including the character and the frequency, was assessed. Furthermore the appetite condition was evaluated. In addition, the effective time of IBS-related pain (which was the time when the scores of pain were less than 70% of that before treatment), the IBS-related pain alleviation time (which was the time when the scores of pain were zero), the effective time of IBS-related diarrhea (which was the time when the scores of stool condition were less than 70% of that before treatment) and the IBS-related diarrhea alleviation time (which was the time when the scores of diarrhea were zero) were recorded in detail. Adverse effects record Participants were required to record any unexpected signs, symptoms and feelings during the treatment period and routine blood, urine and stool tests along with hepatic and renal functions and electrocardiogram (ECG) were examined at admission and after treatment to assess the safety of both groups. Follow-up Four-week follow-up after treatment was undertaken in patients following completion of treatment. Statistical analysis According to our experience with TXNG in treating IBS and other recent studies, the anticipated difference between the placebo and the herbs was predicted. We estimated that for adequate power (80%) to detect a 40% difference on symptom scores at α=0.05 level (1-tailed test), 26 patients were needed in each group. Data were presented according to an intention to treat protocol (ITT), in which patients who withdrew from the trial were recorded as having worsened for categorical items only. Statistical analyses were completed according to ITT or per-protocol population (PP). All data were documented with Epidata 3.0 by two independent individuals and locked after checking. All quantitative data were expressed as mean±standard deviation (SD) and an unpaired Student's t test was used. A Chi-square test and a nonparametric test were performed to calculate differences in qualitative data between the two groups. Data were analyzed using SPSS software (Version 11.5 for windows, Chicago, IL, USA). Statistical significance was pre-set at 0.05 using a 2-tailed test. RESULTS Trial profile and patient characteristics A total of 60 subjects with diarrhea-predominant IBS were recruited during a 10-month period in this study. Thirty were randomized into the TXNG group, and the other 30 into the placebo group (Fig.). Three randomized patients withdrew due to improper recruitment and six patients were withdrawn from the trial after being lost to follow-up (n=3) and ineffective intervention (n=3) during the treatment period. Patients’ data including age, gender, distribution, the duration of disease and the main symptoms of IBS at baseline are shown in Table 2. The homogeneity test between the two groups indicated that the two groups were comparable in all aspects (all P>0.05) in ITT population. Compliance with study medication was high as measured by granule counts and showed no statistical difference between the groups (95.0% for TXNG and 93.0% for the placebo group).Fig.: Trial flow chart. ITT: intention to treat protocol ; PP: per-protocol population.Table 2: Characteristics of patients with diarrhea-predominant IBS at baseline (ITT)Efficacy IBS-related pain measured by the numeric pain intensity scale in the TXNG group significantly decreased compared with the placebo group by the end of therapy (Qcmh=10.51, P=0.0012). A total of 82.7% of the patients reported a reduction in IBS-related pain in the TXNG group compared with 39.3% in the placebo group (P=0.001). Furthermore, there was a statistical difference in the frequency (Qcmh=4.14, P=0.0419) and the duration (Qcmh=7.17, P=0.0074) of abdominal pain between the TXNG group and the placebo group. In addition, IBS-related stool in form or appearance improved in the TXNG group in comparison with the placebo group (Qcmh=9.89, P=0.0017). The stool frequency was significantly decreased in the TXNG group compared with the placebo group (Qcmh=14.57, P=0.0001). Moreover, the stool passage (urgency or feeling of incomplete rectal emptying) in the TXNG group was significantly improved compared with the placebo group (Qcmh=11.59, P=0.0007). We found that the percentage of the loss of appetite in the TXNG group after the treatment was 20.7%, but 42.9% in the placebo group (P=0.064). There were 86.2% of subjects with observable improvement in their IBS-related diarrhea in the TXNG group but 42.9% in the placebo group (P=0.001). There was no statistical difference in either the effective time of IBS-related pain or the effective time of IBS-related diarrhea between the two groups, (6.5 ±4.5) days vs (8.0±5.9) days, 95% CI=(-4.2, 1.2), P=0.2827; (7.5 ± 5.2) days vs (6.9 ± 3.1)days, 95%CI=(-1.6, 2.8), P=0.5900, respectively. However, the IBS-related pain alleviation time and the IBS-related diarrhea alleviation time in the TXNG group were markedly shorter than those in the placebo group, (7.6±4.6) days vs (14.4±4.3) days, 95%CI=(-9.2, -4.4), P=0.000; (9.6±5.2) days vs (12.8±2.2) days, 95%CI=(-5.3, -1.0), P=0.0036. Follow-up assessment After completion of the course of treatment, it was found that the benefits of treatment diminished over time. During the 4-week follow-up, the interval before the IBS-related diarrhea worsened in the patients with an improved status after treatment with TXNG (median=11.0 days, range=6.0 to 20.0 days) was much longer than that in patients treated with the placebo (median=4.0 days, range=1.0 to 20.0 days, P=0.020). There was no statistically significance difference (P=0.12) in the reappearance of IBS-related abdominal pain between the TXNG group (median=9.0 days, range=6.0 to 20.0 days) and the control group (median=3.0 days, range=1.0 to 20.0 days). Safety Over 98% of patients in both groups rated the overall tolerability of the two treatments as “good” or “very good”. Only one patient in the placebo group rated the tolerability of treatment as poor, in whom flush and epigastric pain were described that completely alleviated without any treatment. With regard to laboratory parameters, there were no clinically relevant changes in either of the controlled or the placebo groups. DISCUSSION The diagnosis of IBS is based on symptoms consistent with the disorder and the exclusion of organic disease.9 Therefore the validity and the agreement on the diagnosis of IBS among the researchers are the premise in a trial. Sung's study10 showed that the mean inter-observer agreement rate in diagnosis was 57% for blinded individual assessment, but 80% for individual assessment based on consensual diagnostic criteria. In our study, the Rome II criteria recommended standard criteria were used and all researchers were trained before individual assessment. Thus concordant diagnosis can be reached by mutual understanding and converging opinion among them. IBS patients are a heterogeneous population. Although most patients have extra-intestinal symptoms, including anxiety, fatigue and disturbed sleep, these are not assessed by current diagnostic criteria.3 According to TCM, IBS belongs to the scope of “abdominal pain”, “diarrhea” and “melancholia”. Liver Qi stagnation, spleen Qi deficiency and stagnation of the liver Qi attacking the spleen are three important patterns of TCM in patients with IBS.6 Disorder of the liver Qi influences most easily the transporting and transforming functions of the spleen and stomach, dysfunction of the spleen in transportation, failure of food transforming nutrients, forming pathogenic dampness and lowering to form diarrhea. In addition, stagnation of the liver Qi due to deficiency of the spleen and stomach and grief, anger and mental tension transverse attacking the spleen, disorder the transportation and transformation and lead to diarrhea. In this study, the diarrhea-predominant IBS patients with stagnation of the liver Qi attacking the spleen were selected and the herbal recipe of TXNG was designed for these patients according to TCM principles. In our study, we were able to find clinically relevant differences in abdominal pain and diarrhea between TXNG and placebo in treatment of patients suffering from IBS. Unlike most previous studies of herbal medicine, our positive results are based upon the following reasons. First, the compound prescription termed TXNG consisting of Baishao (radix paeoniae alba), Baizhu (rhizoma atractylodis macrocephalae), Qingpi (pericarpium citri reticulatae viride) and Xiebai (bulbus allii macrostemoni), in which the herbs would have a synergistic interaction, showed a relieving effect on pain and spasms and the inhibition of the gastrointestinal movement. In some other herbal trials, a single herb taken as monotherapy for the treatment of IBS usually was used but not a compound formula.11 Second, we selected the subjects with both the diarrhea-predominant IBS in western medicine and the syndrome of stagnation of the liver Qi attacking the spleen in TCM to keep homogenous the characteristics of the patients in the two groups. Klein12 has criticized trials that are short in trial duration and it has become a truism that long trials are better although there are no experimental data to support this view.13 Importantly and interestingly, Poynard and his collaborators found that short trials can discriminate active treatment from placebo treatment as can long trials.14 In our study, the 3-week length the trial was preceeded with a 2-week run-in period. After 1-week of treatment, the efficacy of TXNG appeared when compared with the placebo but without statistical significance for most of symptoms. Results support a further long trial of treatment with TXNG for IBS to be warranted. In conclusion, this randomized, double-blinded, placebo-controlled trial showed that TXNG as a Chinese herbal formulation may offer an improvement of symptoms to diarrhea-predominant IBS patients with the syndrome of stagnation of the liver Qi attacking the spleen described in TCM. It is the most effective in relieving abdominal pain and diarrhea in those patients, but it needs to be repeated and its mechanisms, identified components and pharmacokinetics need to be explored. Acknowledgement: We are grateful to Dr. SHE Bin for his care of these patients.