Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome

Background Irritable bowel syndrome is the most common disorder diagnosed by gastroenterologists. Although several randomized‐controlled trials have assessed the therapeutic role of antidepressant drugs, there is insufficient evidence to support their use. Aim To compare the effects of low‐dose amitriptyline in the treatment of diarrhoea‐predominant irritable bowel syndrome in a double‐blind randomized‐controlled trial. Methods Fifty‐four patients who fulfilled Rome II criteria for diarrhoea‐predominant irritable bowel syndrome were included in this study. Organic causes were ruled out by standard laboratory and radiological tests, and rectosigmoidoscopy. Patients were randomly assigned to receive either 10 mg amitriptyline daily or placebo. Subjects were followed up for 2 months and symptoms were assessed using a questionnaire. Intention‐to‐treat and per‐protocol analysis was performed. Results Fifty patients completed the study. At 2 months, the amitriptyline group showed greater (P < 0.05) reduction in the incidence of loose stool and feeling of incomplete defecation. Patients receiving amitriptyline showed greater complete response, defined as loss of all symptoms, compared with those receiving placebo (68% vs. 28%, P = 0.01). Adverse effects were similar between the two groups. Conclusion Amitriptyline may be effective in the treatment of diarrhoea‐predominant irritable bowel syndrome and at low dose is well tolerated.     

Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome

Introduction: Rifaximin is a non-absorbable, semisynthetic antibiotic that acts as an inhibitor of bacterial RNA synthesis, with a broad spectrum of antibacterial activity. Due to its poor absorption, rifaximin has an increased exposure to the intestine, thus it is suitable for the treatment of many gastrointestinal (GI) diseases. In irritable bowel syndrome (IBS) pathogenesis, gut microbiota impairment may play a major role. The possibility of modulating intestinal bacteria using antibiotics, in particular, rifaximin, has been demonstrated to improve IBS symptoms in non-constipation subtypes of IBS.

Areas covered: We reviewed the use of rifaximin in diarrhoea-predominant IBS, focusing on its pharmacokinetic characteristics, its absorption in GI disease, its lack of interaction with other drugs and its new extended release formulation.

Expert opinion: Rifaximin, with its low systemic absorption and no clinically significant interactions with other drugs, may represent a treatment of choice for IBS, mainly due to its ability to act on IBS pathogenesis, through the modulation of gut microbiota. Further studies to analyse the effect of rifaximin treatment on the composition of faecal microbiota are warranted. In particular, they need to evaluate whether resistant bacterial strains are selected and whether they are still present in the faecal sample even a long time after therapy.     

Clinical trial: asimadoline in the treatment of patients with irritable bowel syndrome

Background In models of irritable bowel syndrome (IBS), asimadoline, a kappa‐opioid agonist, improves pain and abnormal bowel function. Aim To evaluate the effects of three doses of asimadoline and placebo in subjects with IBS through a double‐blind, randomized, placebo‐controlled trial. Methods Patients were randomly assigned to receive asimadoline 0.15, 0.5, 1.0 mg or placebo BID for 12 weeks. The primary efficacy measure was number of months of adequate relief of IBS pain or discomfort, with a prospective plan to evaluate adequate relief data by entry baseline pain and subtype. Several other endpoints were also evaluated. Results Five hundred and ninety‐six patients were randomized. In the ITT population, statistically significant improvement on the primary endpoint was not seen. However, in diarrhoea‐predominant IBS patients with at least baseline moderate pain, asimadoline (0.5 mg) produced significant improvement on total number of months with adequate relief of IBS pain or discomfort (46.7% vs. 20.0%), adequate relief of IBS symptoms (46.7% vs. 23.0%), pain scores (week 12: ?1.6 vs. ?0.7), pain free days (42.9% vs. 18.0%), urgency and stool frequency (?2.3 vs. ?0.3). In patients with alternating IBS, significant improvement was seen on adequate relief endpoints. Asimadoline was well tolerated. Conclusion Asimadoline warrants further evaluation as a treatment for IBS.     

Clinical trial: effect of active lactic acid bacteria on mucosal barrier function in patients with diarrhoea-predominant irritable bowel syndrome

Background The intestinal permeability is increased in patients with diarrhoea‐predominant irritable bowel syndrome (D‐IBS). Aim To determine the possible efficacy of lactic acid bacteria on the increased intestinal permeability in D‐IBS. Methods Treatment was employed for 4 weeks in a randomized single blind placebo controlled study with 30 D‐IBS patients. Patients were given either probiotic fermented milk (Streptococcus thermophilus, Lactobacillus bulgaricus, Lactobacillus acidophilus and Bifidobacterium Longum) or milk beverage containing no bacteria. The clinical symptoms were scored and intestinal permeability was measured by a triple sugar test before and after treatment. Results Small bowel permeability was measured as the ratio of lactulose and mannitol recovery and colonic permeability was measured as the total mass of sucralose excretion (mg). After probiotics treatment, small bowel permeability decreased significantly from 0.038 (0.024) at baseline to 0.023 (0.020) (P = 0.004), the proportion of patients with increased small bowel permeability was lower than baseline (28.6% vs. 64.3%, P = 0.023). However, colonic permeability improved neither in the probiotics group nor in the placebo group at week 4. Treatment with probiotics significantly decreased the mean global IBS scores compared with the baseline scores (9.62 ± 1.05 vs. 7.64 ± 1.24, P < 0.001). Conclusion Short‐term active lactic acid bacteria treatment for D‐IBS improved mucosal barrier function.     

小剂量阿米替林治疗腹泻型肠易激综合征临床疗效观察

目的探讨小剂量阿米替林对腹泻型肠易激综合征的疗效和耐受性。方法入选64例患者随机分为治疗组和对照组,治疗组每晚给予阿米替林12.5mg,安慰剂组每晚给予维生素C50mg,治疗6周后评价疗效及药物不良反应。结果64例患者全部完成治疗。治疗组症状全部都有改善,症状平均分从2.9分降为0.8分,与治疗前比较差异有统计学意义（P〈0.05）,总有效率为71.9%,与对照组比较差异有统计学意义（P〈0.05）,2组不良反应发生率差异无统计学意义（P〉0.05）。结论小剂量阿米替林治疗腹泻型肠易激综合征有效,患者耐受性好。     

Clinical trial guidelines for pharmacological treatment of irritable bowel syndrome

Appropriate guidelines for clinical trials in irritable bowel syndrome are needed because of the inadequacy of previously performed trials, the use of new and more adequate patient definition, new emerging pathophysiological models and the unique requirements related to the assessment of treatment outcome that, in the absence of a biological marker, can rely only on the evaluation of clinical manifestations. This consensus report highlights the following points. (a) A 4-week period is considered to be adequate to assess drug efficacy for the control of symptoms. (b) For the cyclic and non-life-threatening nature of the disease, a long-term study of 4-6 months or more of active treatment to establish efficacy is considered to be inappropriate in the large majority of patients. (c) In the initial assessment phase of drug efficacy, the withdrawal effect of treatment can be ascertained during a follow-up period prolonged for a sufficient time (4-8 weeks) after stopping treatment. Subsequent trials with proper withdrawal phase design and duration can then ascertain the drug post-treatment benefit. (d) Considering the intermittent clinical manifestations of irritable bowel syndrome, designing trials with on-demand or repeated cycles of treatment could be envisaged. However, the lack of a definition of what constitutes an exacerbation is a major obstacle to the design of such trials. In the absence of an established gold standard, appropriately justified novel trial designs are welcome. (e) Patients eligible for inclusion should comply with the Rome II diagnostic criteria for irritable bowel syndrome. (f) The main efficacy outcome of the treatment should be based on one primary end-point. (g) The primary efficacy end-point could combine, in a global assessment, the key symptoms (abdominal pain, abdominal discomfort, bowel alterations) of irritable bowel syndrome or rate any single symptom for drugs considered to target specific symptoms. (h) A 50% improvement in the primary efficacy end-point seems to be a reasonable definition of a responder.     

Gabapentin reduces rectal mechanosensitivity and increases rectal compliance in patients with diarrhoea-predominant irritable bowel syndrome

BACKGROUND: Gabapentin has been shown to reduce elements of central sensitization in human experimental hyperalgesia. It remains uninvestigated whether gabapentin has beneficial effects for irritable bowel syndrome associated with visceral hypersensitivity. AIMS: To evaluate the effects of gabapentin on sensory and motor function of the rectum in patients with diarrhoea-predominant irritable bowel syndrome. METHODS: Forty patients with diarrhoea-predominant irritable bowel syndrome completed this randomized, double-blind, placebo-controlled, parallel-grouped study. All patients received a barostat study and were subsequently randomized for 5-day treatment with gabapentin 300 mg/day and then 600 mg/day or placebo. On day 6, after subjects had their morning dose, the barostat experiment was repeated. RESULTS: The threshold pressures for bloating, discomfort and pain significantly increased after gabapentin, but not after placebo. Significant increase in the pressure and corresponding wall tension inducing discomfort or pain were observed in the gabapentin group, but not in the placebo group. Rectal compliance significantly increased after gabapentin, but not after placebo. The postprandial increase of rectal tone was not affected by gabapentin. CONCLUSION: Our results show that gabapentin reduces rectal sensory thresholds through attenuating rectal sensitivity to distension and enhancing rectal compliance in diarrhoea-predominant irritable bowel syndrome patients. The clinical efficacy of this drug in irritable bowel syndrome patients warrants investigation.     

洁白胶囊联合阿米替林治疗腹肠易激综合征的临床研究

目的 观察洁白胶囊（抗胃肠功能紊乱药）联合阿米替林治疗腹泻型肠易激综合征（D-IBS）的疗效。方法 143例D-IBS患者随机分成3组，常规治疗组（48例）：每次VI服洁白胶囊0．8g，每天3次；联合治疗组（49例）：常规治疗外，睡前加用阿米替林，第1周，每天12．5mg；第2～4周，每天25mg；对照组（46例）：服用淀粉片每次1片，每天3次，饭后服用。4周为一疗程。结果 治疗1，2，4周后，常规治疗组有效率分别为60．4％，73．9％，77．8％；联合治疗组分别为65．3％，82．6％，93．2％，均明显高于安慰剂组（P〈0．01）；而联合组明显高于常规组（P〈0．05）。结论 洁白胶囊对D-IBS有较好疗效，阿米替林能明显增加洁白胶囊的治疗效果，且病人耐受性较好。     

Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome

Background  Recurrent, watery diarrhoea affects one-third of patients diagnosed with irritable bowel syndrome ('IBS-D'). Idiopathic bile acid malabsorption ('I-BAM') may be the cause.
Aim  To determine the prevalence of I-BAM in patients suffering from IBS-D.
Methods  A systematic search was performed of publications reporting patients presenting with IBS-D type symptoms, who were subsequently confirmed as having I-BAM by SeHCAT scanning.
Results  Eighteen relevant studies, 15 prospective, comprising 1223 patients were identified. Five studies (429 patients) indicated that 10% (CI: 7–13) patients had severe bile acid malabsorption (SeHCAT 7 day retention <5% of baseline value). 17 studies (1073 patients) indicated that 32% (CI: 29–35) patients had moderate bile acid malabsorption (SeHCAT <10%). 7 studies (618 patients) indicated that 26% (CI: 23–30) patients had mild (SeHCAT <15%) bile acid malabsorption. Pooled data from 15 studies showed a dose-response relationship according to severity of malabsorption to treatment with a bile acid binder: response to colestyramine occurred in 96% of patients with <5% retention, 80% at <10% retention and 70% at <15% retention.
Conclusions  Idiopathic adult-onset bile acid malabsorption is not rare. International guidelines for the management of irritable bowel syndrome need to be revised so that clinicians become more aware of this possibility.     

Clinical trial: phase 2 study of lubiprostone for irritable bowel syndrome with constipation

Background Analyses of a trial in constipated patients indicated that lubiprostone may be an effective treatment for irritable bowel syndrome with constipation. Aim To assess the efficacy and safety of three lubiprostone doses for irritable bowel syndrome with constipation. Methods 195 irritable bowel syndrome with constipation patients received daily doses of 16 [8 μg twice daily (b.d.)], 32 (16 μg b.d.) or 48 μg (24 μg b.d.) lubiprostone or placebo b.d. for 3 months. Gastrointestinal parameters were recorded in diaries daily by patients. Results After 1 month, lubiprostone showed significantly greater improvements in mean abdominal discomfort/pain scores vs. placebo (P = 0.023). After 2 months, all lubiprostone groups showed significantly greater improvements in mean abdominal discomfort/pain scores (P ≤ 0.039). After 3 months of treatment, the improvement in each lubiprostone arm was greater than placebo, but the test for trend was no longer significant. Treatment with lubiprostone showed significantly higher rates of gastrointestinal adverse events (P = 0.020), especially diarrhoea and nausea. Conclusion Lubiprostone significantly improved gastrointestinal symptoms of irritable bowel syndrome with constipation at all doses. Higher doses of lubiprostone, especially the 48 μg/day group, were associated with more gastrointestinal adverse events. From these data, the 16 μg/day dose demonstrated the optimal combination of efficacy and safety. These results warrant further study of lubiprostone for treatment of irritable bowel syndrome with constipation patients.     

Randomised clinical trial: the clinical effects of a novel neurokinin receptor antagonist, DNK333, in women with diarrhoea-predominant irritable bowel syndrome

Background Neurokinin receptors may play an important role in the visceral hypersensitivity and exaggerated motor/secretory activity associated with diarrhoea‐predominant irritable bowel syndrome (IBS‐D). Aim To evaluate the effects of DNK333, a novel neurokinin antagonist, in women with IBS‐D. Methods In two consecutive phase II studies, women with IBS‐D were randomised to twice‐daily (b.d.) DNK333 25 mg, DNK333 100 mg or placebo for 2 weeks (Trial 1), or DNK333 25 mg b.d. or placebo for 4 weeks (Trial 2). Primary efficacy variables studied were change from baseline of stool form at week 2, and satisfactory relief of IBS‐related abdominal pain/discomfort and global IBS‐D symptoms. Secondary efficacy variables, pharmacokinetics and safety were also evaluated. Results In total, 315 subjects were randomised. There were no statistically significant differences between treatment groups for the primary efficacy variables. However, analysis of combined data from both trials revealed significant differences favouring DNK333 25 mg over placebo for satisfactory relief of IBS‐related abdominal pain/discomfort and global IBS‐D symptoms. Trends favouring improvement with DNK333 25 mg vs. placebo were seen for all secondary efficacy variables. DNK333 had a safety profile similar to placebo. Conclusions DNK333 25 mg b.d. appears to be effective and well tolerated in women with IBS‐D. Further studies with neurokinin antagonists are warranted.     

西酞普兰治疗肠易激综合征46例

目的:探讨西酞普兰治疗肠易激综合征(IBS)的临床疗效。方法:将91例IBS病人随机分成2组,治疗组46例[男性18例,女性28例,年龄(42±s10)a],应用西酞普兰20mg,po,qd。对照组45例[男性20例,女性25例,年龄(43±9)a],应用谷维素30mg,po,tid,疗程均为4wk。结果:治疗组的总有效率为93%,对照组为49%(P<0.01)。治疗后4wk,2组汉密尔顿焦虑量表(HAMA)和汉密尔顿抑郁量表(HAMD)总分均显著降低(P<0.01),2组间比较治疗组优于对照组(P<0.01)。结论:西酞普兰是治疗IBS的安全有效药物。     

Controlled clinical trial of sedative-anticholinergic drugs in patients with the irritable bowel syndrome.

We studied 16 patients with long-standing irritable bowel syndrome of moderate severity using a controlled, double-blind crossover method. Five sedative-anticholinergic drug combinations and a placebo were tested. The subjective response was assessed with four subjective methods to include an increasing number of response variables. The patients preferred 30 mg phenobarbital plus 8 mg belladonna (P & B) to placebo (P = 0.02). Five of ten patients were helped "some" or "a lot" with placebo, while ten of 15 were helped "some" or "a lot" with P & B (P = 0.07). The ten prominent-symptoms method revealed that subjective symptoms such as nervousness, sleep difficulties, and tiredness were experienced as greater problems than diarrhea. The factor analysis method documented a strong placebo response. Simpler evaluation methods such as drug preference and a five-choice method appear more likely to show a positive drug effect, while the inclusion of a larger number of variables appears to emphasize the placebo portion of the response. These observations may help explain some of the apparent discrepancies between the conclusions of some controlled clinical trials and subsequent clinical experience.     

抗抑郁药物治疗肠易激综合征

目的 探讨抗抑郁药物氟伏沙明对肠易激综合征(IBS)患者的疗效.方法 40例IBS患者随机分为内科常规治疗加用氟伏沙明组和仅用内科常规治疗的对照组,疗程8周,观察比较用药前后肠易激综合征症状评估、排便频率和大便性状.结果 治疗组的显效率为50.0%、总有效率为90.0%,对照组分别为20.0%和65.0%,两者存在显著性差异(P＜0.05).结论 IBS患者常规内科治疗的同时联用抗抑郁药物氟伏沙明临床有效,能明显改善胃肠症状.     

曲美布汀治疗肠易激综合征的临床疗效

目的 :观察曲美布汀治疗肠易激综合征(IBS)的临床疗效。方法 :参照罗马Ⅱ标准 ,选择 60例IBS病人 ,随机分成治疗组和对照组 ,每组 30例。对照组男性 12例 ,女性 18例 ,年龄 (33±s 16)a。治疗组男性 13例 ,女性 17例 ,年龄 (31± 12 )a。 2组均给予谷维素 (2 0mg ,po ,tid)、维生素B1(2 0mg ,po ,tid)、维生素C (0 .2 g ,po ,tid)。治疗组加用曲美布汀 2 0 0mg ,po ,tid ,疗程 2wk。观察治疗前后IBS腹痛、腹泻、便秘、腹胀的情况。结果 :治疗组wk 1总有效率 67% ,wk 2总有效率 83%。wk 2腹痛缓解率 90 % ,腹泻缓解率 89% ,便秘缓解率77% ,腹胀缓解率 81%。无明显不良反应。结论 :曲美布汀是治疗IBS安全有效的药物     

Clinical economics review: irritable bowel syndrome

The ubiquitous nature of irritable bowel syndrome (IBS), coupled with a lack of good treatment options, has created the impression that the condition must represent a large drain on health-care resources. The literature certainly appears to support this view but is largely based on patients seen in referral centres (10–15%) and it may not be appropriate to extrapolate these data to the IBS population as a whole (85–90%).
In addition to reviewing such literature that exists on the economics of IBS, this paper contains some new data, which suggest that the direct costs of the condition, certainly in the UK, may not be quite as high as has previously been assumed. This may be partly due to factors such as the low cost of the drugs used to treat the condition and the tendency for many patients to stop consulting because of disenchantment with the inadequacies of current therapy. Conversely, the indirect and intangible costs of the disorder appear to be much greater, but these burdens obviously do not have such an impact on those responsible for purchasing and providing health care for IBS sufferers.
Paradoxically, if a new, effective therapy for IBS were forthcoming, the situation could change dramatically, especially if it involved a new drug. Any such agent would inevitably be more expensive than anything available today, leading to a potentially dramatic escalation in the direct costs of this disorder.     

马来酸曲美布汀联合门诊森田疗法治疗肠易激综合征的临床研究

目的 :观察马来酸曲美布汀联合门诊森田疗法治疗肠易激综合征 (irritablebowelsyndrome ,IBS)的临床疗效。方法 :10 8例患者随机分为 2组。马来酸曲美布汀组 5 4例 :2 0 0mg马来酸曲美布汀 ,po ,tid ,配合门诊森田心理疗法 ,治疗前、后以焦虑自评量表 (SAS)和抑郁自评量表 (SDS)评定疗效 ;对照组5 4例 :仅用 2 0 0mg马来酸曲美布汀 ,po ,tid ,2组疗程均为 4周。结果 :马来酸曲美布汀组和对照组总有效率分别为 87.0 4 %与 72 .2 2 % ,马来酸曲美布汀组明显优于对照组 (P <0 .0 5 )。马来酸曲美布汀组治疗后SAS、SDS评分与对照组比较均有明显下降(P <0 .0 1)。马来酸曲美布汀组 6月复发率与对照组比较明显降低 (P <0 .0 1)。结论 :马来酸曲美布汀联合门诊森田疗法是治疗肠易激综合征更有效的治疗方法。