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Although the pathogenesis of irritable bowel syndrome is still poorly understood, altered intestinal motor function and visceral hypersensitivity have been shown to be important aetiological factors.1 Abnormal gastrointestinal motor function has frequently been reported in irritable bowel syndrome, not only in the colon, but also in the small intestine.2–4
The literature on colonic motor abnormalities in irritable bowel syndrome is partly conflicting, but older publications suggest that the incidence of segmenting contractions is increased in constipation-predominant and decreased in diarrhoea-predominant irritable bowel syndrome.5, 6 In addition to abnormalities in segmenting contractions, abnormalities in high-amplitude propagated contractions (HAPCs) have been found in patients with irritable bowel syndrome.7 In those patients with diarrhoea, an increased incidence of HAPCs was observed, whereas constipated patients had less HAPCs than normal.8, 9
In addition, colonic tone, as measured by the barostat technique, appears to be abnormal in irritable bowel syndrome. In particular, the post-prandial increase in tone was less prominent and shorter in duration in patients with irritable bowel syndrome than in healthy subjects.8, 10
Recent evidence supports the hypothesis that, in a subset of patients with irritable bowel syndrome, symptoms are related to visceral hypersensitivity. Rectal balloon distension has been used as a model to examine visceral sensitivity, and has shown that patients with irritable bowel syndrome are more sensitive to rectal distension than healthy volunteers.11–15 However, the relationship between altered visceral sensitivity and abnormal motility has yet to be established.16
5-Hydroxytryptamine (5-HT) plays an important role in the regulation of gastrointestinal motility and perception.17 In diarrhoea-predominant patients with irritable bowel syndrome, the post-prandial increase in 5-HT plasma concentration was found to be significantly exaggerated.18
Alosetron is a potent and selective antagonist at the 5-HT3 receptor.19 Placebo-controlled clinical trials have shown that alosetron is of benefit in female patients with diarrhoea-predominant irritable bowel syndrome. In the clinical trials, alosetron was well tolerated and improved abdominal pain and discomfort, urgency, stool frequency and stool consistency.20–22 Alosetron increases the compliance of the descending colon to distension, and could thereby contribute to changes in perception of colonic distension and improvement in symptoms of irritable bowel syndrome.23 Alosetron has been shown to have no overall effect on the orocaecal transit time, but it increases the whole gut transit time as a result of increasing the left colonic transit time.24
The effect of alosetron on phasic left colonic contractions and HAPCs has not previously been studied.
The aim of this study was to examine the effects of orally administered alosetron (4 mg twice daily) on left colonic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers. Because colonic motility in general is highly variable throughout a 24-h period and HAPCs are infrequent colonic events, ambulatory colonic manometry over a 24-h period was used.
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This is the first study evaluating the effect of alosetron on left colonic phasic motility in non-constipated patients with irritable bowel syndrome and healthy volunteers using prolonged ambulatory manometry.
Although multiple comparisons were performed in this study and comparisons were not adjusted for multiplicity, we feel that the following conclusions are justified within the context of the exploratory analyses: (i) alosetron affects left colonic motility in the periprandial period in patients with irritable bowel syndrome as well as in healthy volunteers; (ii) alosetron increases the HAPC frequency in patients with irritable bowel syndrome and the propagation length in all subjects; (iii) treatment with alosetron is accompanied by a decrease in stool frequency and consistency score; and (iv) non-constipated patients with irritable bowel syndrome on alosetron appear to have less constipation and report less abdominal pain and discomfort compared to healthy volunteers.
Most studies on colonic motility in patients with irritable bowel syndrome have been performed in a laboratory setting during a short period of time and after a total colonic lavage.5–11 In the present study, we used a prolonged ambulatory manometric technique with the advantage of recording multiple HAPCs in each subject after refilling of the colon.
This study demonstrates that 24-h colonic manometry is feasible and well tolerated. However, the failure rate of about 40% remains one of the major problems of this technique. Half of this failure rate was caused by technical problems, such as failure of catheter placement, transducer failure, catheter expulsion and perianal pain.
Periprandial motility is thought to be changed in patients with irritable bowel syndrome, and other studies suggest a post-prandial increase in 5-HT plasma concentration in patients with diarrhoea-predominant irritable bowel syndrome.6–8, 17, 18 Periprandial motility was studied during the evening meal on day 7 because this meal was more than 26 h after partial colonic cleaning and was combined with alosetron or placebo.
HAPCs were analysed during the daytime period on day 7, because it is known that hardly any HAPCs occur during sleep. During the 24-h period of day 7, only 2.0% of the HAPCs were counted during the night-time in the placebo treatment period and 2.3% of HAPCs were counted during the night-time in the alosetron treatment period. We were especially interested in the effect of alosetron on the diurnal occurrence of HAPCs: in healthy volunteers, HAPCs occur more often in the first part of the day.26 For this reason, we analysed the total daytime period as well as the first and second half of the daytime period separately.
We did not take the menstrual cycle into account for practical reasons. In our opinion, there is not sufficient evidence to support the view that the influence of hormones on left colonic motility significantly increases the intrinsic variability relative to that measured in men.27
We found no significant differences between non-constipated patients with irritable bowel syndrome and healthy volunteers in terms of the periprandial motility index or 24-h HAPC frequency, regardless of whether the treatment received was placebo or alosetron. This might be due to patient selection, because non-constipated patients with irritable bowel syndrome can be considered as a mixture of diarrhoea-predominant, alternating diarrhoea and constipation, as well as pain-predominant irritable bowel syndrome patients.
Our healthy subjects had a somewhat higher number of HAPCs during the control arm of the study. However, there was a wide variation of HAPC number in the healthy volunteer group, with two subjects having a very high number of HAPCs (28 and 30) on day 7. We decided not to exclude these two outliers. Without these two subjects, the effect of alosetron on HAPC frequency would have been more convincing.
Recently, colonic transit through the ascending and transverse colon has been shown to be related to stool weight.28 The whole gut transit time, which is correlated to the stool form, and the stool frequency were significantly different in patients with irritable bowel syndrome reporting constipation compared with those reporting diarrhoea.29 Houghton et al. showed that alosetron increases left colonic transit time.24 Our results concerning stool characteristics (decreased stool frequency and consistency during alosetron treatment) are in line with the observed slowing of colonic transit.
The literature suggests that a shortened colonic transit time, increased stool frequency and decreased stool consistency can be explained by a higher incidence of anally directed mass movements produced by a greater number of HAPCs and less segmenting non-propagated colonic contractions.7, 9, 10, 30, 31
Serotonin plays a role in physiological and pathological states in the human colon.18, 32–34 Bearcroft et al. showed an increase in serotonin release in response to a meal in female patients with diarrhoea-predominant irritable bowel syndrome.18 In a study with the 5-HT3 receptor antagonist ondansetron, it was found that selective blockade may blunt the post-prandial tonic and phasic motor response in healthy volunteers.30 In contrast, in this study, it appears that alosetron slightly increased the frequency and amplitude of left colonic contractions.
HAPCs are the major motor events in the colon producing mass movements. HAPCs are related to defecation and the feeling of urge. The highest frequency is noted after meals and after awakening in the morning. Less HAPCs are recorded in the late afternoon and during the night.26 Fewer HAPCs were counted in constipated patients, while a higher number were seen in a small group of patients with functional diarrhoea.9, 10
At present, no studies exist describing the effect of 5-HT3 receptor antagonists on HAPC frequency.17, 32, 33 The results of our study show that 5-HT3 receptor blockade seems to increase the HAPC frequency and propagation length, and that there may be more HAPCs in non-constipated patients with irritable bowel syndrome on alosetron during the second half of the day.
The paradox of a higher HAPC frequency and greater propagation distance accompanied by a decreased stool frequency and stool consistency, suggesting a delay in colonic transport, is difficult to explain. One might speculate that the incidence of non-propagating, segmenting contractions is increased by alosetron, leading to a longer colonic transit time and a higher stool consistency. This might further be promoted by retardation of proximal colonic emptying by alosetron, which was shown in patients with carcinoid diarrhoea.34 Furthermore, alosetron increases the compliance of the descending colon to distension, which might have a negative effect on faecal transport.23 Finally, the observed change in consistency may also be caused by an alosetron-induced decrease in water secretion in the small bowel.34 More HAPCs might just be needed to transport the high-viscosity faecal mass across the highly resistant left colonic region.
The most frequently reported adverse effect during alosetron treatment was constipation. Ten out of 12 subjects who experienced constipation on alosetron were healthy volunteers. This suggests that the positive results of alosetron in non-constipated patients with irritable bowel syndrome might partly be related to a shift to a normal defecation frequency and consistency.
The reduction in the number of days with urgency that was reported in a large placebo-controlled study is likely to be related to a decreased faecal mass, a decreased rectal compliance, restoring the reservoir function of the colon and rectum, and a reduced rectal sensory score.21, 23, 35, 36
Alosetron has been shown to reduce abdominal pain in patients with irritable bowel syndrome, particularly in those with loose or watery stools.20, 21 The effect of alosetron on visceral perception might be accomplished by an increase in compliance or by directly influencing colonic afferents.23, 35, 36
In conclusion, the 5-HT3 receptor antagonist alosetron appears to marginally increase left colonic periprandial phasic motility. Alosetron also increases the number and propagation distance of HAPCs, which is paradoxically accompanied by a decrease in stool frequency and a firming of stool consistency.