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.     

Effects of alosetron on gastrointestinal transit time and rectal sensation in patients with irritable bowel syndrome

BACKGROUND: Alosetron, a 5-HT3-receptor antagonist, relieves abdominal pain and improves bowel function in non-constipated, female patients with irritable bowel syndrome. 5-HT3 antagonists delay colonic transit, increase colonic compliance, and increase small intestinal water absorption. AIM: To evaluate the effects of alosetron on gastrointestinal and colonic transit, rectal compliance and rectal sensation in irritable bowel syndrome. METHODS: A double-blind, placebo-controlled, two-dose study of alosetron was performed in 25 non-constipated irritable bowel syndrome patients, with paired studies before and after 4 weeks of treatment with placebo (n=5), 1 mg alosetron (n=10) or 4 mg (n=10) alosetron b.d. Gastrointestinal and colonic transit were measured by scintigraphy. Rectal compliance and sensation were assessed by rectal balloon distention with a barostat. RESULTS: There was a trend (P=0.06) for 1 mg alosetron to increase rectal compliance (median pressure at half maximum volume 11 mmHg after alosetron vs. 15.6 mmHg before alosetron). The 1 mg b.d. alosetron dose non-significantly retarded proximal colonic transit. Alosetron and placebo reduced sensory scores relative to baseline values; none of the changes induced by alosetron was significant relative to placebo. CONCLUSIONS: Alosetron had no significant effect on gastrointestinal transit or rectal sensory and motor mechanisms in non-constipated irritable bowel syndrome patients in this study. Alosetron's effects on colonic sensorimotor function and central sensory mechanisms deserve further evaluation.     

Review article: colonic sensorimotor physiology in health, and its alteration in constipation and diarrhoeal disorders

Aim:

To review the physiology of colonic motility and sensation in healthy humans and the pathophysiological changes associated with constipation and diarrhoea.

Source:

Medline Search from 1965 using the index terms: human, colonic motility, sensation, pharmacology, neurohormonal control, gastrointestinal transit, constipation, diarrhoea and combinations of these.

Results:

In health, the ascending and transverse regions of colon function as reservoirs to accommodate ileal chyme and the descending colon acts as a conduit; the neuromuscular functions and transmitters control colonic motility and sensation and play pivotal roles in disorders associated with constipation and/or diarrhoea. Disorders of proximal colonic transit contribute to symptoms in idiopathic constipation, diarrhoea-predominant irritable bowel syndrome and carcinoid diarrhoea. Colonic function in patients presenting with constipation is best assessed clinically by colonic transit time using radiopaque markers ingested orally. Measurements of colonic contractility are less useful clinically but they can help identify motor abnormalities including colonic inertia; in some patients with irritable bowel syndrome, abdominal pain, urgency and diarrhoea are temporally associated with high amplitude contractions, which originate in the proximal colon and traverse the distal conduit at very high propagation velocities. Visceral hypersensitivity contributes to the urgency and tenesmus in irritable bowel syndrome and inflammatory bowel disease. Colonic motility and sensation can be reduced by anticholinergic agents, somatostatin analogues and 5HT₃ antagonists.

Conclusion:

Physiological and pharmacological studies of the human colon have provided new insights into the pathophysiology of colonic disorders, and offer possibilities of novel therapeutic approaches for constipation or diarrhoea associated with colonic motor or sensory dysfunction.

     

Lipid-induced colonic hypersensitivity in irritable bowel syndrome: the role of 5-HT3 receptors

BACKGROUND: Irritable bowel syndrome patients demonstrate colonic hypersensitivity after duodenal lipid infusion. AIM: To investigate the role of 5-hydroxytryptamine-3 (5-HT3) receptors in this sensory component of the gastrocolonic response in irritable bowel syndrome. METHODS: Fifteen female patients with diarrhoea-predominant irritable bowel syndrome completed a trial with the 5-HT3 receptor antagonist alosetron (1 mg b.d.) or placebo (b.d.) over 15 days, followed by the alternative treatment. Each treatment period was followed by a colonic distension trial before and after duodenal lipids. Changes in colonic thresholds, tone and compliance and viscerosomatic referral pattern after lipids were compared between treatments. RESULTS: With placebo, the colonic thresholds after lipids were significantly reduced for all studied sensations, whereas, with alosetron, the thresholds were significantly reduced only for first sensation and discomfort, but not for gas and pain. The reductions in thresholds did not differ significantly between treatments, but the pain threshold after alosetron tended to be less reduced compared with placebo (P = 0.10). The effects of lipids on tone, compliance and viscerosomatic referral pattern were unaffected by alosetron relative to placebo. CONCLUSIONS: 5-HT3 receptor antagonism reduces the lipid-induced colonic hypersensitivity in irritable bowel syndrome. However, 5-HT3 receptors do not seem to be the principal mediator, but may be a cofactor for the exaggerated sensory component of the gastrocolonic response in irritable bowel syndrome.     

Anti-hyperalgesic effect of octreotide in patients with irritable bowel syndrome

BACKGROUND: Octreotide has been found to be beneficial in the treatment of chronic pain, although the mechanisms underlying its therapeutic effect are incompletely understood. AIMS: To assess the effect of octreotide on perceptual responses to rectal distension in irritable bowel syndrome patients and healthy controls at baseline and following the experimental induction of rectal hyperalgesia. METHODS: In study 1, rectal perception thresholds for discomfort were determined in seven irritable bowel syndrome patients and eight healthy controls on three separate days using a computer-controlled barostat. Subjects received saline, low-dose and high-dose octreotide in a random double-blind fashion. In study 2, perceptual responses to rectal distension were obtained in nine irritable bowel syndrome patients and seven controls before and after repetitive high-pressure mechanical sigmoid stimulation. RESULTS: Octreotide increased the discomfort thresholds in irritable bowel syndrome patients, but not in controls, without changing rectal compliance. Repetitive sigmoid stimulation resulted in decreased rectal discomfort thresholds in the patient group only. In irritable bowel syndrome patients, octreotide prevented the sensitizing effect of repetitive sigmoid stimulation on rectal discomfort thresholds. CONCLUSIONS: Octreotide effectively increased discomfort thresholds in irritable bowel syndrome patients, but not in controls, at baseline and during experimentally induced rectal hyperalgesia. These findings suggest that octreotide exerts primarily an anti-hyperalgesic rather than analgesic effect on visceral perception.     

Towards identifying optimal doses for alpha-2 adrenergic modulation of colonic and rectal motor and sensory function

RATIONALE: Visceral sensation and motility are important in functional gut disorders and are partly controlled by adrenergic innervation. OBJECTIVES: To characterize the alpha2-adrenergic control of motor and sensory function of descending colon and rectum. METHODS: In 32 healthy volunteers, we assessed compliance, fasting and postprandial tone, and sensations of gas, urgency and pain during phasic distentions. Each subject received one agent at clinically approved doses: clonidine (0.05, 0.1, 0.2 or 0.3 mg p.o. ); or the alpha2 antagonist yohimbine (0.0125 mg, 0.05 mg, 0.125 mg or 0.2 mg intravenously and infusion over 2.5 h). RESULTS: Clonidine increased colonic and rectal compliance, and reduced tone, pain, gas sensation and rectal urgency. Clonidine showed large pairwise differences in sensation and motility between 0.05 and 0.1 mg doses, which did not interfere with the colon's motor response to feeding. Conversely, yohimbine dose-dependently altered the compliance curve, increased tone and sensations of gas, pain and urgency. Drug effects in the colon were more marked at low distensions; alpha2 modulation of rectal sensation was observed at all levels of distension. CONCLUSIONS: alpha2-adrenergic mechanisms modulate colorectal sensations and motility; at doses as low as 0.05 mg, clonidine reduced colorectal sensation while the tone response to feeding was preserved. These studies provide insight into the potential use of alpha2 agents in disease states.     

Oesophageal hypersensitivity is associated with features of psychiatric disorders and the irritable bowel syndrome

BACKGROUND: Twenty per cent of patients with heartburn do not respond to proton pump inhibitors (PPIs). Many have normal oesophageal acid exposure. We hypothesized that such PPI non-responders have heightened oesophageal sensation, and that oesophageal hypersensitivity is associated with psychiatric features including somatization and anxiety. AIM: To compare oesophageal sensation in subjects with heartburn categorized by response to PPI, and to correlate oesophageal sensation with psychiatric features. METHODS: Twenty-one PPI responders, nine PPI non-responders and 20 healthy volunteers completed questionnaires of psychiatric disorders and gastrointestinal symptoms. Subjects underwent oesophageal sensory testing with acid perfusion and balloon distension. RESULTS: Healthy volunteers displayed higher thresholds for sensation and discomfort from balloon distension than heartburn subjects (sensation P = 0.04, discomfort P = 0.14). Psychiatric disorders were associated with increased intensity of sensation (P = 0.02) and discomfort from acid (P = 0.01). Somatization was associated with increased discomfort from balloon distension (P = 0.006). Features of irritable bowel syndrome were associated with increased sensation and discomfort. CONCLUSIONS: Heartburn subjects tend to have heightened oesophageal sensation, suggesting that oesophageal hypersensitivity may persist despite therapy with PPI. Oesophageal hypersensitivity is associated with features of psychiatric disease and with the irritable bowel syndrome, which might partly explain the aetiology of heartburn symptoms that are refractory to PPI.     

Alosetron

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.     

Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome

Background:

Visceral hypersensitivity plays a major role in the pathophysiology of irritable bowel syndrome, as shown by balloon distension studies. 5-HT3 receptors on afferent nerves may modulate visceral sensitivity and be the target of new treatments for irritable bowel syndrome.

Aim:

To evaluate the effects of alosetron, a potent and selective 5-HT3 antagonist, on the perception of colonic distension by patients with irritable bowel syndrome, and on the colonic compliance to distension with a barostat.

Methods:

Twenty-five irritable bowel syndrome patients were included in a randomized double-blind parallel group trial; data were available for 22 (Rome criteria; 48 ± 11 years; 13 men and nine women). Patients were treated for 7 days with placebo (n = 6), alosetron 0.25 mg b.d. (n = 8) or alosetron 4 mg b.d. (n = 8). On day 6, a barostat bag was placed in the left colon. On day 7, after an overnight fast, isobaric phasic distensions were performed (4 mmHg steps, 5 min) up to the step triggering a sensation of abdominal pain.

Results:

Groups were comparable at inclusion (age, sex, symptoms, bowel habits). There were no differences between treatment groups in pressure recorded within the bag at the time of first sensation of abdominal pain. However, bag volumes were significantly increased. At the first sensation threshold, median volume differences of 61 mL and 90 mL (P = 0.028) were recorded with alosetron 0.25 mg b.d. and 4 mg b.d., respectively. At the threshold of abdominal pain, these differences were 71 mL (P = 0.039) and 84 mL (P = 0.017). Colonic compliance increased from 5.9 mL/mmHg on placebo to 7.6 mL/mmHg on alosetron 0.25 mg b.d. and to 9.8 mL/mmHg (P = 0.034) on alosetron 4 mg b.d.

Conclusion:

Alosetron increases the compliance of the colon to distension, and could thereby contribute to changes in perception of colonic distension and improvement in the symptoms of irritable bowel syndrome.

     

Gut-focused hypnotherapy normalizes disordered rectal sensitivity in patients with irritable bowel syndrome

BACKGROUND: We have previously shown that hypnotherapy alters rectal sensitivity in some patients with irritable bowel syndrome. However, this previous study used incremental volume distension of a latex balloon, which might be susceptible to subject response bias and might compromise the assessment of compliance. In addition, the study group was symptomatically rather than physiologically defined. AIM: To assess the effect of hypnotherapy on rectal sensitivity in hypersensitive, hyposensitive and normally sensitive irritable bowel syndrome patients using a distension technique (barostat) that addresses these technical issues. METHODS: Twenty-three irritable bowel syndrome (Rome I) patients (aged 24-72 years) were assessed before and after 12 weeks of hypnotherapy in terms of rectal sensitivity, symptomatology, anxiety and depression. Normal values for sensitivity were established in 17 healthy volunteers (aged 20-55 years). RESULTS: Compared with controls, 10 patients were hypersensitive, seven hyposensitive and six normally sensitive before treatment. Following hypnotherapy, the mean pain sensory threshold increased in the hypersensitive group (P = 0.04) and decreased in the hyposensitive group, although the latter failed to reach statistical significance (P = 0.19). Normal sensory perception was unchanged. Sensory improvement in the hypersensitive patients tended to correlate with a reduction in abdominal pain (r = 0.714, P = 0.07). CONCLUSION: Hypnotherapy improves abnormal sensory perception in irritable bowel syndrome, leaving normal sensation unchanged.     

Relationship between symptoms and hypersensitivity to rectal distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity is considered an important pathophysiological mechanism in irritable bowel syndrome, yet its relationship to symptoms is unclear. AIM: To detect possible associations between symptoms and the presence of hypersensitivity to rectal distension in patients with irritable bowel syndrome. METHODS: Ninety-two irritable bowel syndrome patients and 17 healthy volunteers underwent a rectal barostat study. The association between specific irritable bowel syndrome symptoms and the presence of hypersensitivity was examined using Area under the Receiver Operating Characteristic curves. RESULTS: Irritable bowel syndrome patients had significantly lower thresholds for discomfort/pain than healthy volunteers: 24 (18-30) and 30 (27-45) mmHg above minimal distending pressure, respectively. Forty-one patients (45%) showed hypersensitivity to rectal distension. Proportions of patients with different predominant bowel habits were similar in hypersensitive and normosensitive subgroups (diarrhoea predominant: 39 and 41%, respectively; alternating type: 27 and 28%, respectively; constipation predominant: 34 and 31%, respectively). Severe abdominal pain was more frequent in hypersensitive, compared with normosensitive patients (88% vs. 67%, P = 0.02), but none of the individual irritable bowel syndrome symptoms could accurately predict the presence of hypersensitivity, as assessed by Area under the Receiver Operating Characteristic curve analysis. CONCLUSIONS: Hypersensitive and normosensitive irritable bowel syndrome patients present with comparable, heterogeneous symptomatology. Therefore, selection based on clinical parameters is unlikely to discriminate individual irritable bowel syndrome patients with visceral hypersensitivity from those with normal visceral sensitivity.     

Effect of asimadoline, a kappa opioid agonist, on pain induced by colonic distension in patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity plays a major role in irritable bowel syndrome pathophysiology. Opioid kappa receptors on afferent nerves may modulate it and be the target for new irritable bowel syndrome treatments. AIM: This study evaluated the effect of the kappa opioid agonist asimadoline on perception of colonic distension and colonic compliance in irritable bowel syndrome patients. METHOD: Twenty irritable bowel syndrome female patients (Rome II criteria; 40 +/- 13 years) and hypersensitivity to colonic distension (Pain threshold < or = 32 mmHg) were included in a randomized double-blind cross-over trial comparing the effect of a single oral dose of asimadoline 0.5 mg or placebo on sensory thresholds (defined as a constant and sustained sensation) elicited by left colon phasic distension (5 mmHg steps, 5 min) up to a sensation of abdominal pain. Colonic compliance was compared by the slope of the pressure-volume curves. RESULTS: On asimadoline, pain threshold (mean +/- s.d.) (29.8 +/- 7.2 mmHg) was higher than on placebo (26.3 +/- 7.8 mmHg), difference not statistically significant (P = 0.1756, ANOVA). Area under curve of pain intensity rated at each distension step was significantly lower on asimadoline (89.3 +/- 33.9, ANOVA) than on placebo (108.1 +/- 29.7) (P = 0.0411). Thresholds of perception of nonpainful distensions were not altered on asimadoline, as compared with placebo. Colonic compliance was not different on placebo and asimadoline. CONCLUSION: Asimadoline decreases overall perception of pain over a wide range of pressure distension of the colon in irritable bowel syndrome patients, without altering its compliance. These data suggest that further studies should explore the potential benefit of asimadoline in treatment of pain in irritable bowel syndrome patients.     

Effect of long-term treatment with octreotide on rectal sensitivity in patients with non-constipated irritable bowel syndrome

BACKGROUND: Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown. AIM: To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients. METHODS: Forty-six non-constipated irritable bowel syndrome patients (52% female, 19-63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly. RESULTS: Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, P < 0.05). In contrast, abdominal pain and defecation frequency were not affected. CONCLUSIONS: Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms.     

Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome

The effect of granisetron, a specific 5-hydroxytryptamine 3-receptor antagonist, on the anorectal responses to rectal distension and a 1000-calorie meal was assessed in 12 patients with irritable bowel syndrome. Each patient was studied on three occasions, receiving intravenously either 40 mcg/kg granisetron, 160 mcg/kg granisetron or normal saline. Granisetron caused a dose-dependent reduction in rectal sensitivity, manifested by an increase in the threshold volumes at which the sensations of gas, desire to defecate, urgency and discomfort were perceived. This reached significance for all sensations at the higher dose level (P < 0.01). No significant changes in anal pressures, rectal compliance or distension-induced motor activity occurred following drug administration. A dose-dependent reduction in post-prandial motility was observed following intravenous granisetron and this was highly significant at 160 mcg/kg (P= 0.005). These results suggest that the 5 hydroxytryptamine receptor antagonists may have a therapeutic role in patients with irritable bowel syndrome.     

Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist

BACKGROUND: No currently available treatment provides consistent relief of irritable bowel syndrome. Colonic sensory and motor function are modulated partly through 5HT3-receptors. AIM: To evaluate effects of the 5HT3-receptor antagonist, alosetron, in irritable bowel syndrome. METHODS: Randomized, double-blind, placebo-controlled, dose-ranging (1, 2, 4, 8 mg b.d. alosetron), 12-week trial in 370 patients with diarrhoea-predominant or alternating constipation and diarrhoea irritable bowel syndrome. Weekly measurement of adequate relief was the key end-point; other irritable bowel syndrome symptoms were collected daily using an electronic phone system. RESULTS: Alosetron (1 mg or 2 mg b.d.) significantly (P < 0.05 vs. placebo) increased the proportion of females, but not males, reporting adequate relief. Stool consistency, frequency and percentage days with urgency improved over placebo (P < 0.05) within the first month with all doses of alosetron, and persisted throughout the trial with all doses in female patients. With 1 mg b.d. alosetron, females had improved stool consistency and urgency within the first week, and adequate relief and improved stool frequency within the first 2 weeks. There was no consistent improvement in bowel function among male patients. CONCLUSION: In female irritable bowel syndrome patients with predominant diarrhoea or alternating constipation and diarrhoea, alosetron is effective in treatment of abdominal pain and discomfort and bowel-related symptoms.     

Selective 5-hydroxytryptamine antagonism: a role in irritable bowel syndrome and functional dyspepsia?

Background: Abnormalities of gut motility and visceral pain perception are both thought to be involved in the pathogenesis of irritable bowel syndrome and may be susceptible to modulation by drugs affecting the various 5-HT receptor subtypes. The aim of this study was to investigate the therapeutic potential of a 5-HT₃ antagonist in irritable bowel syndrome.
Methods: Fifty patients with irritable bowel syndrome were treated with ondansetron, a highly selective 5-HT₃ antagonist, in a double-blind, placebo-controlled cross-over study. In addition to assessing its effect on the classical symptoms of irritable bowel syndrome (abdominal pain, distension and disordered bowel habit) its effect on symptoms often seen in irritable bowel syndrome, but more commonly associated with functional dyspepsia, was also examined.
Results: Ondansetron reduced bowel frequency ( P =0.035) and improved stool consistency ( P =0.002) in diarrhoea predominant irritable bowel syndrome and did not cause a deterioration of bowel habit in constipation predominant subjects. No statistically significant improvement was seen for abdominal pain or distension, although those patients who did respond were approximately twice as likely to be taking ondansetron than placebo. It was also found that ondansetron significantly improved the upper gastrointestinal symptoms of post-prandial epigastric discomfort ( P =0.008), flatulence ( P =0.022) and heartburn ( P =0.003).
Conclusion: The results of this study justify evaluation of the therapeutic potential of selective 5-HT antagonists in both functional dyspepsia and irritable bowel syndrome.     

5-HT4 receptor antagonism in irritable bowel syndrome: effect of SB-207266-A on rectal sensitivity and small bowel transit

BACKGROUND: Pre-clinical studies indicate that the 5-hydroxytryptamine (5-HT)4 receptor may be involved in the pathophysiology of irritable bowel syndrome and that antagonism of this receptor may be an effective therapeutic strategy. AIM: To investigate the effects of SB-207266-A, a selective 5-HT4 receptor antagonist on rectal sensitivity and small bowel transit in patients with irritable bowel syndrome. METHODS: Eighteen patients with diarrhoea-predominant irritable bowel syndrome and a history of increased rectal sensitivity were randomized to receive either SB-207266-A (20 mg) or placebo for 10 days. Following a washout period, patients were then crossed over to receive the alternative therapy for 10 days. Rectal sensitivity and orocaecal transit time were assessed on day 10 of each treatment period. In addition, patients were asked whether they had experienced any changes in their symptoms. RESULTS: Fifteen patients completed the study. SB-207266-A significantly increased orocaecal transit time towards normal (placebo: 5.3 h (4.0-7.2 h), mean (IQR) vs. SB-207266-A: 6.5 h (4.8-8.0 h); P=0.027) and tended to decrease rectal sensitivity (volume to discomfort 89 mL (60-150 mL), geometric mean (IQR) vs. 107 mL (75-150 mL); P=0.134). Eleven out of 15 patients reported symptomatic improvements with SB-207266-A but none with placebo. SB-207266-A was well tolerated. CONCLUSION: Our results support a role for the 5-HT4 receptor in the pathophysiology of irritable bowel syndrome and suggest that the selective 5-HT4 antagonist, SB-207266-A, is worthy of further evaluation in this disorder.     

A randomized controlled trial of a probiotic,VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome

AIM: To investigate the effects of a probiotic formulation, VSL#3, on gastrointestinal transit and symptoms of patients with Rome II irritable bowel syndrome with predominant diarrhoea. METHODS: Twenty-five patients with diarrhoea-predominant irritable bowel syndrome were randomly assigned to receive VSL#3 powder (450 billion lyophilized bacteria/day) or matching placebo twice daily for 8 weeks after a 2-week run-in period. Pre- and post-treatment gastrointestinal transit measurements were performed in all patients. Patients recorded their bowel function and symptoms daily in a diary during the 10-week study, which was powered to detect a 50% change in the primary colonic transit end-point. RESULTS: There were no significant differences in mean gastrointestinal transit measurements, bowel function scores or satisfactory global symptom relief between the two treatment groups, pre- or post-therapy. Differences in abdominal bloating scores between treatments were borderline significant (P = 0.09, analysis of covariance). Further analysis revealed that abdominal bloating was reduced (P = 0.046) with VSL#3 [mean post- minus pre-treatment score, - 13.7; 95% confidence interval (CI), - 2.5 to - 24.9], but not with placebo (P = 0.54) (mean post- minus pre-treatment score, - 1.7; 95% CI, 7.1 to - 10.4). With the exception of changes in abdominal bloating, VSL#3 had no effect on other individual symptoms: abdominal pain, gas and urgency. All patients tolerated VSL#3 well. CONCLUSION: VSL#3 appears to be promising in the relief of abdominal bloating in patients with diarrhoea-predominant irritable bowel syndrome. This is unrelated to an alteration in gastrointestinal or colonic transit.     

Effect of alosetron on left colonic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers

BACKGROUND: Alosetron is a 5-hydroxytryptamine-3 receptor antagonist reducing symptoms in female patients with diarrhoea-predominant irritable bowel syndrome, and is known to increase the colonic transit time. AIM: To study the effect of alosetron on left colonic phasic motility in ambulant non-constipated patients with irritable bowel syndrome and healthy volunteers. METHODS: In a double-blind, randomized, crossover design, 10 patients with irritable bowel syndrome and 12 sex- and age-matched volunteers were treated for two 7-day periods with alosetron, 4 mg b.d., or placebo b.d. On day 6 of each treatment period, a six-channel solid-state manometric catheter was positioned in the left colon and 24 h motility was studied on day 7. The periprandial phasic motility around dinnertime was evaluated in the descending and sigmoid colon. The high-amplitude propagated contraction frequency and characteristics were calculated. RESULTS: Alosetron appeared to increase the overall periprandial frequency in the sigmoid colon (P=0.043) and the mean amplitude of colonic contractions in the descending colon (P=0.007). The high-amplitude propagated contraction frequency was higher on alosetron during the second half of the day for patients with irritable bowel syndrome (P=0.002), with increased mean propagation length of high-amplitude propagated contractions (P=0.001). The stool frequency (P=0.024) and stool consistency score (P=0.002) were decreased by alosetron. CONCLUSIONS: The 5-hydroxytryptamine-3 receptor antagonist alosetron marginally increased left colonic periprandial phasic motility. Alosetron increased the number and propagation length of high-amplitude propagated contractions, which were paradoxically accompanied by a decrease in stool frequency and a firming of stool consistency.     

Pregabalin inhibits accelerated defecation and decreased colonic nociceptive threshold in sensitized rats

Pregabalin, a ligand of α₂δ subunits of voltage-gated calcium channels, reduces visceral hypersensitivity associated with irritable bowel syndrome. However, effects of pregabalin on bowel function are not well described. We investigated the effects of pregabalin on bowel dysfunction and colonic nociceptive threshold in sensitized rats. Increased fecal pellet output was evoked by non-ulcerogenic stress. Decreased colonic nociceptive threshold was induced in separate rats by administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the proximal colon. Fecal pellet output was significantly increased during 2 h restraint stress. Oral pregabalin (10-100 mg/kg, p.o.) inhibited this increased fecal output dose-dependently, but did not change fecal output in naïve rats. The response threshold to distension of the non-inflamed distal colon was significantly decreased seven days after TNBS administration. An anti-hyperalgesic effect of pregabalin (30-100 mg/kg, p.o.) that opposed the decreased colonic nociceptive threshold in TNBS-sensitized rats was observed, but nociceptive thresholds were not changed in naïve rats. Moreover, pregabalin was more potent in reducing disturbed defecation compared with reduction in nociceptive threshold to distension in TNBS-sensitized rats. This is the first report that pregabalin modulates stress-induced defecation in rats. These data indicate that pregabalin can ameliorate both altered defecation and decreases in colonic nociceptive threshold, suggesting that pregabalin might warrant investigation for the treatment of irritable bowel syndrome.