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.     

Influence of citalopram, a selective serotonin reuptake inhibitor, on oesophageal hypersensitivity: a double-blind, placebo-controlled study

Background Tricyclic antidepressants, which have multiple pharmacological influences, have a therapeutic effect in non-cardiac chest pain, but selective serotonin reuptake inhibitors have a single pharmacological effect. Aim To evaluate the acute effect of citalopram on oesophageal hypersensitivity. Methods On two separate occasions, 10 healthy subjects (seven men, mean age 25 years) with established oesophageal hypersensitivity, underwent oesophageal manometry with evaluation of mechanical and chemical sensitivity. Subjects received placebo or citalopram 20 mg i.v. in a randomized, crossover, double-blind fashion. Results Citalopram did not alter oesophageal motility. Citalopram significantly increased the threshold inducing first perception (4.6+/-0.3 vs. 6.7+/-0.4 mL, P<0.005) and discomfort (8.6+/-0.4 vs. 9.9+/-0.6 mL, P<0.01) during balloon distention. It also significantly prolonged the acid perfusion time to induce perception of heartburn (6.0+/-0.9 vs. 10.7+/-0.6 min, P<0.005) and discomfort (12.2+/-0.8 vs. 16.7+/-0.7 mL, P<0.001). Seven subjects experienced a retrosternal sensation during edrophonium provocation with placebo, and this was reduced to two of 10 after citalopram (P=0.02). Conclusions Acute administration of citalopram significantly lowers chemical and mechanical oesophageal sensitivity in oesophageal hypersensitivity, without altering the motility.     

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.     

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.     

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.     

Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5-hydroxytryptamine type-3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT₃ antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea-predominant irritable bowel syndrome were studied. A multilumen barostatmanometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function. We conclude that in diarrhoea-predominant irritable bowel syndrome there is reduced rectal compliance and the rectum is abnormally sensitive to a pressure stimulus, but this is not altered by 5HT₃-blockade with ondansetron at the dose used.     

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.     

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.

     

Anxiety but not depression determines health care-seeking behaviour in Chinese patients with dyspepsia and irritable bowel syndrome: a population-based study

AIMS: To study the prevalence of dyspepsia and irritable bowel syndrome and the effects of co-existing anxiety and depression on health care utilization by a population survey in Chinese. METHODS: Ethnic Chinese households were invited to participate in a telephone survey using a validated bowel symptom questionnaire and the hospital anxiety and depression scale. Gastrointestinal symptoms were classified as dyspepsia and irritable bowel syndrome according to the Rome I criteria and gastro-oesophageal reflux disease by the presence of weekly heartburn or acid regurgitation. The anxiety and depression scores were compared between patients who sought medical attention and those who did not, using multiple logistic regression analysis. RESULTS: One thousand, six hundred and forty-nine subjects completed the interview (response rate, 62%). The population prevalences of dyspepsia, irritable bowel syndrome and gastro-oesophageal reflux disease were 18.4%, 4.1% and 4.8%, respectively. Dyspepsia and irritable bowel syndrome were associated with anxiety, depression, medical consultation, sick leave and adverse effects on social life. The degree of anxiety was an independent factor associated with health care-seeking behaviour in both dyspeptics (P = 0.003) and irritable bowel syndrome patients (P = 0.036). CONCLUSIONS: Irritable bowel syndrome and dyspepsia are associated with anxiety, depression, significant social morbidity, health care utilization and days off work. Anxiety is an independent factor in determining health care utilization in patients with dyspepsia and irritable bowel syndrome.     

Review article: abdominal bloating and distension in functional gastrointestinal disorders--epidemiology and exploration of possible mechanisms

Background A sensation of abdominal bloating, sometimes accompanied by an increase in girth (distension), is one of the most common and most intrusive features of functional bowel disorders. Aim To conduct a systematic, evidence‐based review of the epidemiology and pathophysiology of abdominal bloating and its relationship to distension. Methods The terms bloating, distension, functional bowel, irritable bowel syndrome, constipation and diarrhoea were searched on MEDLINE up to 2006. References from selected articles and relevant abstracts were also included. Results Approximately 50% of irritable bowel syndrome patients with bloating also experience an increase in abdominal girth and this is more pronounced with constipation than diarrhoea. Bloating appears to be more frequently associated with visceral hypersensitivity, whereas distension is more often related to hyposensitivity and delayed transit. Although there is little evidence for excessive gas as a cause of bloating, gas infusion studies suggest that handling of gas may be impaired in irritable bowel syndrome and there may also be abnormal relaxation of the anterior abdominal musculature in these patients. Conclusions There is unlikely to be a single cause for bloating and distension, which probably have different, but overlapping, pathophysiological mechanisms. Relieving constipation might help distension, but the treatment of bloating may need more complex approaches involving sensory modulation.     

Irritable bowel, smoking and oesophageal acid exposure: an insight into the nature of symptoms of gastro-oesophageal reflux

BACKGROUND: In gastro-oesophageal reflux disease, oesophageal acid exposure correlates with symptoms but explains only a small fraction of their variance. AIMS: To elucidate the effects of irritable bowel syndrome and smoking on gastro-oesophageal reflux disease symptoms and to clarify whether they modulate the relationship between oesophageal acid exposure and symptoms. METHODS: The relationship between oesophageal acid exposure, irritable bowel syndrome (Rome I criteria), smoking status and symptoms was investigated in patients with a normal gastroscopy who underwent a 24-h oesophageal pH monitoring. RESULTS: Of 256 patients with gastro-oesophageal reflux disease, 16% were smokers and 50% met the criteria for irritable bowel syndrome (irritable bowel syndrome+). The extent of oesophageal acid exposure was unrelated to smoking or irritable bowel syndrome status. Oesophageal acid exposure, irritable bowel syndrome status and current smoking independently predicted symptoms. Irritable bowel syndrome and smoking modulated the effect of oesophageal acid exposure on symptoms: oesophageal acid exposure was predictive of symptoms only in non-smokers. However, irritable bowel syndrome was a significant predictor of symptoms both in smokers and in non-smokers. Smoking was associated with symptoms only in irritable bowel syndrome+, while oesophageal acid exposure was associated with symptoms irrespective of irritable bowel syndrome status. CONCLUSIONS: In patients with non-erosive gastro-oesophageal reflux disease, smoking and irritable bowel syndrome independently predicted symptoms, without affecting the extent of oesophageal acid exposure. The relationship between oesophageal acid exposure and symptoms was affected significantly, and in opposite directions, by smoking and irritable bowel syndrome.     

Review article: evaluation of drugs in experimental gut distension models

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristic of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT₃ receptor antagonist, alosetron.     

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.     

Risk factors for gastro-oesophageal reflux disease symptoms: a community study

AIM: To examine the prevalence of gastro-oesophageal reflux disease symptoms and potential risk factors among community subjects. METHODS: A questionnaire was sent to 4000 subjects, stratified by age, gender and ethnicity to be representative of the local population. Gastro-oesophageal reflux disease symptoms were defined as at least weekly heartburn or acid regurgitation. RESULTS: 2231 responded (59%), 691 refused to participate and seven were incomplete. 1533 (41%) were evaluable (637 male, mean age 51 years, range: 20-80). The prevalence of gastro-oesophageal reflux disease symptoms was 21%. Smoking, excess alcohol, irritable bowel syndrome, increasing body mass index, a family history of upper gastrointestinal disease, increasing Townsend deprivation index, anticholinergic drugs (all P < 0.0001), weight gain, antidepressant drugs, inhaled bronchodilators, no educational attainment (all P < 0.01), south Asian origin (P = 0.02) and manual work (P < 0.05) were associated with gastro-oesophageal reflux disease symptoms. Multivariate logistic regression revealed increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin (all P < 0.0001), smoking, excess alcohol, no educational attainment and anticholinergic drugs (all P < 0.01) were independently associated with gastro-oesophageal reflux disease symptoms. CONCLUSIONS: Frequent gastro-oesophageal reflux disease symptoms affect 21% of the population. Increasing body mass index, a family history of upper gastrointestinal disease, irritable bowel syndrome, south Asian origin, smoking, excess alcohol, social deprivation and anticholinergic drugs are independently associated with gastro-oesophageal reflux disease symptoms.     

Positive association between gastro-oesophageal reflux disease and irritable bowel syndrome in a Chinese population

BACKGROUND: Gastro-oesophageal reflux disease and irritable bowel syndrome are common diseases which may be related. AIM: To examine the association between gastro-oesophageal reflux disease and irritable bowel syndrome in Chinese population in Hong Kong. METHODS: Randomly selected ethnic Chinese were invited to participate in a telephone survey in 1996. Gastro-oesophageal reflux disease was defined as subjects having heartburn and/or acid regurgitation once weekly or more. Irritable bowel syndrome was diagnosed according to the Rome I criteria. The association between gastro-oesophageal reflux disease and irritable bowel syndrome was calculated using a statistical model which allows the odds ratio to be measured. RESULTS: One thousand six hundred and forty-nine subjects completed the interview (response rate 62%). The population prevalence of gastro-oesophageal reflux disease and irritable bowel syndrome were 5% and 4%, respectively. Thirteen per cent of subjects with gastro-oesophageal reflux disease and 11% with irritable bowel syndrome suffered from both gastro-oesophageal reflux disease and irritable bowel syndrome. The OR of having gastro-oesophageal reflux disease and irritable bowel syndrome together was estimated to be 3 (95% CI: 1.05, 6.27) indicating a positive association between the two diseases. This association occurred predominantly in male subjects [OR = 9.3, (95% CI: 2.3, 26.2)] but not as strong in females [OR = 1.5, (95% CI: 0.3, 4.3)]. Younger subjects were statistically more prone to the two diseases. CONCLUSIONS: There is a positive association between gastro-oesophageal reflux disease and irritable bowel syndrome, and their association occurs predominantly in male subjects.     

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.     

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.     

A single dose of ranitidine 150 mg modulates oesophageal acid sensitivity in patients with functional heartburn

BACKGROUND: The rapid onset and symptomatic response to histamine-2 receptor antagonists prior to the pharmacological effect on acid secretion suggests a different mechanism of action. AIM: To determine if ranitidine decreases oesophageal sensitivity to chemical and mechanical stimulation, potentially via oesophageal histamine receptors. METHODS: A total of 18 patients with functional heartburn received oral ranitidine 150 mg b.d. or placebo for 7 consecutive days in a double-blind randomized crossover design and underwent Barostat balloon distention and Bernstein acid infusion on study day 1 (90 min postdose) and study day 7. First sensation and pain were recorded and pain severity was rated on a 5-point Likert scale and a 100 mm visual analogue scale. Least square mean values were generated and one-tailed t-tests were performed. RESULTS: After a single dose of ranitidine 150 mg, time to pain with oesophageal acid infusion was increased by 29% (P < 0.05) and visual analogue scale and Likert scores were decreased by 20% (P < 0.06) and 23% (P < 0.02), respectively compared with placebo. After 1 week of ranitidine, positive alterations in sensory parameters persisted. Balloon distention sensory parameters were not altered by ranitidine. CONCLUSIONS: Ranitidine significantly decreased oesophageal sensitivity to acid. Failure of ranitidine to improve balloon sensory parameters supports existence of multiple sensory pathways in the oesophagus.     

Effect of the kappa agonist fedotozine on perception of gastric distension in healthy humans

Background and Aim : Gastric hypersensitivity to mechanical distension has been observed in functional dyspepsia, but no drug is available that specifically acts on gastric afferent pathways to decrease gastric nociception. The aim of this study was to assess the effect of fedotozine, a synthetic ligand for peripheral kappa receptors, on human gastric sensitivity.
Methods : Twenty-seven healthy volunteers were randomized to receive either fedotozine (30 mg t.d.s.) or a placebo, for 7 days. On day 7, the effects of fedotozine were tested on discomfort threshold and gastric compliance during graded isobaric and isovolumic distensions. In 16 of these subjects, the effect of this drug was tested on somatic sensitivity. In 10 other healthy volunteers the effect of fedotozine on gastric distension-induced inhibition of the RIII reflex, a process closely related to visceral sensitivity, was also studied.
Results: During isobaric distensions, the discomfort threshold was significantly higher in subjects on fedotozine than in those on placebo (14.4±0.92 vs. 12.0±1.13 mmHg; P =0.04). Compared to placebo, fedotozine did not modify gastric compliance and somatic sensitivity. Fedotozine also reduced the inhibition of the RIII reflex induced by gastric distension.
Conclusion: Fedotozine decreases gastric sensitivity to distension by exerting specific action on gastric afferent pathways.     

Baclofen decreases acid and non-acid post-prandial gastro-oesophageal reflux measured by combined multichannel intraluminal impedance and pH

BACKGROUND: Omeprazole controls acid but not non-acid reflux. The GABA B agonist baclofen decreases acid reflux through the inhibition of transient lower oesophageal sphincter relaxations (TLESRs) and should similarly decrease non-acid reflux. Using combined multichannel intraluminal impedance and pH (MII/pH), we compared acid and non-acid reflux after placebo and baclofen. METHODS: Nine healthy volunteers and nine heartburn patients underwent two 2-h studies of combined MII/pH in right lateral decubitus after a refluxogenic meal in random order: on placebo and after baclofen 40 mg p.o. Tracings were analysed for acid and non-acid reflux episodes, re-reflux and symptoms in the heartburn patients. RESULTS: In normal subjects baclofen significantly reduced the median number of episodes of acid (7 vs. 1, P = 0.02), non-acid (2 vs. 0, P = 0.005), and all reflux combined (10 vs. 2, P = 0.006); re-reflux was not reduced (0 vs. 0, P = N.S.). In heartburn patients, baclofen significantly decreased the median number of episodes of acid (15 vs. 6, P = 0.004), non-acid (4 vs. 2, P = 0.003), re-reflux (2 vs. 0, P = 0.02), and all reflux combined (23 vs. 8, P = 0.004); it also reduced the median number of acid-related (9 vs. 1, P = 0.008) and non-acid-related (1 vs. 0, P = 0.04) symptoms. CONCLUSIONS: Baclofen reduces post-prandial acid and non-acid reflux and their associated symptoms. GABA B agonists may have a role in treating GERD.