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.

Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation.

OBJECTIVE: Patients with irritable bowel syndrome (IBS) show evidence of altered perceptual responses to visceral stimuli, consistent with altered processing of visceral afferent information by the brain. In the current study, brain responses to anticipated and delivered rectal balloon distension were assessed. METHODS: Changes in regional cerebral blood flow were measured using H2(15)O-water positron emission tomography in 12 nonconstipated IBS patients and 12 healthy control subjects. Regional cerebral blood flow responses to moderate rectal distension (45 mm Hg) and anticipated but undelivered distension were assessed before and after a series of repetitive noxious (60-mm Hg) sigmoid distensions. RESULTS: Brain regions activated by actual and simulated distensions were similar in both groups. Compared with control subjects, patients with IBS showed lateralized activation of right prefrontal cortex; reduced activation of perigenual cortex, temporal lobe, and brain stem; but enhanced activation of rostral anterior cingulate and posterior cingulate cortices. CONCLUSIONS: IBS patients show altered brain responses to rectal stimuli, regardless of whether these stimuli are actually delivered or simply anticipated. These alterations are consistent with reported alterations in autonomic and perceptual responses and may be related to altered central noradrenergic modulation.

Perceptual responses in patients with inflammatory and functional bowel disease.

BACKGROUND AND AIMS: Enhanced visceral sensitivity following a transient inflammatory process in the gut has been postulated as an aetiological mechanism of irritable bowel syndrome (IBS). In this study we compared perceptual responses to rectosigmoid distension in patients with mild chronic inflammation of the rectum (ulcerative colitis (UC)) and patients without mucosal inflammation (IBS) to determine if chronic low grade mucosal inflammation may be a plausible explanation for rectosigmoid hypersensitivity reported in both IBS and UC patients. METHODS: UC disease activity was quantified using activity index scores. Perception thresholds for discomfort during rectosigmoid distension were compared between 11 UC patients with quiescent or mild disease activity, 18 IBS patients, and 13 healthy controls. RESULTS: Although UC activity index scores negatively correlated with perceptual thresholds for discomfort (r=-0.76, p=0.016), UC patients had higher discomfort thresholds compared with IBS patients and controls before (p=0.02) and after (p<0.001) a noxious sigmoid conditioning stimulus. CONCLUSIONS: Rectal perception was attenuated in UC but enhanced in IBS. In chronic mild inflammation, activation of antinociceptive mechanisms may prevent the development of visceral hyperalgesia. Low grade mucosal inflammation alone is unlikely to be responsible for symptoms in functional gastrointestinal disorders.

Gender differences in regional brain response to visceral pressure in IBS patients.

In two experiments including a total of 30 irritable bowel syndrome patients, symptom-mimicking rectal pressure stimuli elicited changes in regional neural activation as measured by positron electron tomography (PET) cerebral blood flow images. Although most stimuli were not rated as painful, rectal pressure increased regional cerebral blood flow (rCBF) in areas commonly associated with somatic pain, including the anterior cingulate, insula, prefrontal cortex, thalamus, and cerebellum. Despite similar stimulus ratings in male and female patients, regional activations were much stronger for males. In both experiments, rectal pressure activated the insula bilaterally in males but not in females. Insula activation was associated most strongly with objective visceral pressure, whereas anterior cingulate activation was associated more with correlated ratings of subjective discomfort. The insula is discussed as a visceral sensory cortex. Several possible reasons for the insula gender effect are proposed.

The evolving neurobiology of gut feelings.

The bi-directional communication between limbic regions and the viscera play a central role in the generation and expression of emotional responses and associated emotional feelings. The response of different viscera to distinct, emotion-specific patterns of autonomic output is fed back to the brain, in particular to the cingulofrontal convergence region. Even though this process unfolds largely without conscious awareness, it plays an important role in emotional function and may influence rational decision making in the healthy individual. Alterations in this bi-directional process such as peripheral pathologies within the gut or alterations at the brain level may explain the close association between certain affective disorders and functional visceral syndromes.

Review article: gender-related differences in functional gastrointestinal disorders.

Many functional gastrointestinal disorders and other chronic visceral pain disorders such as interstitial cystitis and chronic pelvic pain are more common in women than in men. In irritable bowel syndrome (IBS) there is a 2:1 female to male ratio in prevalence of symptoms in community samples. Female irritable bowel syndrome patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms. While animal studies have clearly demonstrated gender-related differences in pain perception and antinociceptive mechanisms, unequivocal evidence for gender-related differences in human pain perception or modulation has only been provided recently. Gender-related differences may be related to constant differences in the physiology of pain perception, such as structural or functional differences in the visceral afferent pathways involved in pain transmission or modulation, and/or they may be related to fluctuations in female sex hormones. Preliminary evidence suggests that female irritable bowel syndrome patients show specific perceptual alterations in regards to rectosigmoid balloon distension and that they show differences in regional brain activation measured by positron emission tomography. This preliminary evidence suggests that gender-related differences in symptoms and in the perceptual responses to visceral stimuli exist in IBS patients and can be detected using specific stimulation paradigms and neuroimaging techniques.

Symptoms and visceral perception in patients with pain-predominant irritable bowel syndrome.

OBJECTIVE: Abdominal pain is thought to be a hallmark of the irritable bowel syndrome (IBS), although currently used symptom criteria do not differentiate between abdominal pain and discomfort. By focusing on viscerosensory symptoms, we sought to determine: 1) which type of symptoms are most commonly reported by IBS patients, and 2) whether patients who report pain as their most bothersome symptom differ in clinical, psychological, and physiological characteristics. METHODS: A total of 443 consecutive new patient referrals to a tertiary referral center for functional gastrointestinal disorders who met symptom criteria for IBS were given validated, psychometric, health status, and bowel symptom questionnaires containing specific questions regarding the patients' predominant viscerosensory gastrointestinal symptom. Of these patients, 155 (35%) also met criteria for functional dyspepsia. A representative subset of the total IBS patient population (n = 58) underwent evaluation of perceptual responses to controlled rectal distension before and after a noxious sigmoid conditioning stimulus. RESULTS: Viscerosensory symptoms clustered into four groups: 1) abdominal pain, 2) bloating-type discomfort, 3) sensation of incomplete rectal evacuation, and 4) extraabdominal (chest pain or pressure and nausea). A total of 66% of patients reported gas as one of their viscerosensory symptoms, whereas 60% reported abdominal pain as one of their symptoms. Only 29% rated abdominal pain as their most bothersome symptom, whereas bloating-type symptoms were listed by 60% as most bothersome. Although pain predominance did not correlate with the severity of gastrointestinal or psychological symptoms, there was a significant correlation with the development of rectal hypersensitivity in response to the sigmoid conditioning stimulus. CONCLUSIONS: In a tertiary referral population of IBS patients: 1) abdominal pain is reported by only one third of patients as their most bothersome viscerosensory symptoms; and 2) pain-predominance correlates with development of rectal hypersensitivity after a noxious sigmoid stimulus.

Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans.

BACKGROUND & AIMS: Chronic tissue injury in the esophagus associated with gastroesophageal reflux disease may result in sensitization of afferent pathways mediating mechanosensitivity and chemosensitivity. The aim of this study was to evaluate the sensitivity to intraluminal acid and to distention of the esophagus in patients with mild-to-moderate gastroesophageal reflux disease. METHODS: Perceptual responses to intraluminal acid perfusion and to esophageal distention and pressure volume relationships were evaluated in 10 healthy volunteers and in 11 patients. Mechanosensitivity was evaluated with a barostat using unbiased distention protocols and verbal descriptor ratings of sensations. Chemosensitivity to acid was determined at baseline and after a 1-month treatment of acid suppression. RESULTS: Patients showed enhanced perception of acid perfusion but not of esophageal distension. Chemosensitivity but not mechanosensitivity was correlated with reflux symptoms and with the degree of endoscopically shown tissue injury at baseline. Tissue injury was not associated with altered compliance. CONCLUSIONS: Mild-to-moderate chronic tissue injury in gastroesophageal reflux disease differentially affects mechanosensitive and chemosensitive afferent pathways. Chronic acid reflux by itself is not likely to play a role in reported esophageal hypersensitivity to distention in patients with noncardiac chest pain.

Subtypes of constipation predominant irritable bowel syndrome based on rectal perception.

BACKGROUND: Patients who complain of constipation can be divided into those who have lost the natural call to stool, but develop abdominal discomfort after several days without a bowel movement (no urge); and those who experience a constant sensation of incomplete evacuation (urge). AIMS: To determine whether the two groups differ in symptoms, colonic transit, and perceptual responses to controlled rectal distension. METHODS: Forty four patients with constipation were evaluated with a bowel symptom questionnaire, colonic transit (radiopaque markers), and rectal balloon distension. Stool (S) and discomfort (D) thresholds to slow ramp (40 ml/min) and rapid phasic distension (870 ml/min) were determined with an electronic distension device. Fifteen healthy controls were also studied. RESULTS: All patients had Rome positive irritable bowel syndrome (IBS); 17 were no urge and 27 urge. Mean D threshold to phasic rectal distensions was 28 (3) mm Hg in no urge, 27 (3) mm Hg in urge (NS), but higher in the control group (46 (2) mm Hg; p < 0.01). Sixty seven per cent of no urge and 69% of urge were hypersensitive for D. Slow ramp distension thresholds were higher in no urge (S: 26 (3); D: 45 (4) mm Hg) compared with urge (S: 16 (2); D: 31 (3) mm Hg; p < 0.01), or with controls (S: 15 (1); D: 30 (3); p < 0.01). CONCLUSIONS: Hyposensitivity to slow rectal distension is found in patients with IBS who complain of constipation and have lost the call to stool even though their sensitivity to phasic distension is increased.

Evidence for two distinct perceptual alterations in irritable bowel syndrome.

BACKGROUND: Visceral hyperalgesia has been implicated as a factor contributing to symptom generation in irritable bowel syndrome (IBS). However, previous studies using intestinal balloon distension have used psychophysical procedures which do not provide adequate and unbiased measures of visceral sensitivity. METHODS: Three psychophysical tasks were examined in 45 patients with IBS (positive Rome criteria) and 14 controls using rectal balloon distension with a computerised distension device. Discomfort threshold and tolerance were assessed during an ascending series of phasic pressure stimuli and during an interactive threshold tracking procedure. In addition, stimulus response functions were generated from intensity and unpleasantness ratings of the rectal distensions. RESULTS: Discomfort threshold and tolerance for the ascending stimuli were significantly lower for the patients with IBS compared with the controls. In contrast, discomfort thresholds during the tracking procedure and stimulus response curves for the ascending series were not different between the groups. A factor analysis of the psychophysical data was consistent with the presence of two distinct and unrelated perceptual alterations related to rectal distension: hypervigilance for visceral stimuli, manifested as lowered response criteria for using the descriptor "discomfort"; and rectal hypersensitivity, manifested as a lower discomfort threshold and left shift of the stimulus response curves. CONCLUSIONS: Patients with IBS as a group have a greater propensity to label visceral sensations negatively and show a lower tolerance for rectal balloon distension. A subgroup of patients also have baseline rectal hypersensitivity, assessed by unbiased measures of discomfort threshold and stimulus intensity judgements.

Sigmoid afferent mechanisms in patients with irritable bowel syndrome.

Up to 60% of patients with IBS have lowered perception thresholds in the rectum to balloon distension. The current study sought to test the hypothesis that IBS patients with normal perception thresholds in the rectum show hypersensitivity of afferent pathways in the sigmoid colon. Eleven healthy normal subjects and eight IBS patients with normal rectal perception thresholds underwent a balloon distension protocol in the sigmoid and rectum. Discomfort thresholds, receptive relaxation, compliance, and referral patterns were measured. Although IBS patients had significantly lower discomfort thresholds in the sigmoid when measured as volume, pressure, and wall tension, thresholds were similar to normals. Receptive relaxation and dynamic compliance were significantly decreased in IBS patients in the sigmoid. Referral patterns were similar during sigmoid distention in IBS patients in comparison to normals. Despite normal perception thresholds in rectum and sigmoid, IBS patients show evidence for alterations in rectosigmoid afferent mechanisms. In the sigmoid, this is seen in the form of reduced reflex relaxation and compliance and in the rectum in the form of altered viscerosomatic referral.

Repetitive sigmoid stimulation induces rectal hyperalgesia in patients with irritable bowel syndrome.

BACKGROUND & AIMS: Only a fraction of patients with irritable bowel syndrome (IBS) show hypersensitivity to rectal distention. The current study sought to determine if repetitive high-pressure stimulation of sigmoid mechanoreceptors modulates perception of rectal pain and discomfort. METHODS: In 14 patients with IBS and 11 healthy controls, perception thresholds for discomfort and pain during rectal sensory tracking and verbal descriptor ratings of the perceived intensity of a rectal tonic stimulus were obtained before and after repetitive high-pressure mechanical sigmoid stimulation. Gastrointestinal and psychological symptoms were assessed by questionnaires. RESULTS: Despite heterogeneity in baseline rectal sensitivity in patients with IBS, after sigmoid stimulation, 100% of patients, regardless of baseline sensitivity, developed rectal hyperalgesia manifested by at least two of the following three criteria: lowered thresholds for pain and discomfort and increased viscerosomatic referral and lower abdominal discomfort outlasting the experimental stimulation. This pattern of responses was not observed in any of the healthy controls. CONCLUSIONS: In patients with IBS, repetitive stimulation of sigmoid splanchnic afferents results in the development of central sensitization manifested as hyperalgesia and increased viscerosomatic referral during rectal distention and as spontaneous rectosigmoid hyperalgesia in the absence of applied stimuli. Repetitive sigmoid contractions may induce rectosigmoid hyperalgesia in patients with IBS.

Regional cerebral activity in normal and pathological perception of visceral pain.

BACKGROUND & AIMS: To characterize the cerebral processing of noxious visceral events, changes in regional cerebral blood flow associated with perception of intestinal pain were examined. METHODS: The effects of rectal pressure stimuli on regional cerebral blood flow were assessed with 15O-water positron emission tomography (PET) in 12 subjects, half with irritable bowel syndrome (IBS). PET scans were obtained at baseline and during both actual and simulated delivery of anticipated stimuli. Changes in regional cerebral blood flow were interpreted using statistical parametric mapping and region of interest methods of analysis. RESULTS: In healthy subjects, perception of pain during actual or simulated delivery of painful stimuli was significantly associated (P < 0.01) with activity of the anterior cingulate cortex (ACC; Brodmann's areas 24 and 32), whereas no ACC response to perception of nonpainful stimuli was observed. In patients with IBS, the ACC failed to respond to the same stimuli, whereas significant activation (P < 0.01) of the left prefrontal cortex (maximal in Brodmann's area 10) was seen. CONCLUSIONS: The perception of acute rectal pain is associated with activation of the ACC in healthy subjects, and patients with IBS show an aberrant brain activation pattern both during noxious rectal distention and during the anticipation of rectal pain.

Characterization of afferent mechanisms in ileoanal pouches.

OBJECTIVES: The afferent innervation of ileoanal pouches plays an important role in perception and in reflex regulation of pouch function. We aimed to characterize afferent nerve function in ileoanal pouches and thereby explain the clinical presentation of patients with such pouches. METHODS: In eight patients who underwent surgery for active ulcerative colitis, perception of balloon distention of the pouch was measured using an electronic visceral distention device. In addition, pouch compliance and ileoanal reflex function were determined. Studies were performed during the initial stage of pouch creation (pouch without connection to proximal ileum, study 1) and a mean of 6.6 wk (range = 2-12 wk) after the second stage of the surgery (proximal ileum in continuity with the pouch, study 2). Nine normal volunteers made up the control group. RESULTS: When expressed as intrapouch pressure, thresholds for stool and discomfort sensations were similar in patients with a pouch and controls. However, during ramp distention, patients with a pouch had a lower volume threshold for stool sensation (143 +/- 45 ml vs 300 +/- 30 ml, p = 0.009). The initial sensation of discomfort was experienced in the perineum at the S3 dermatome in all eight patients. At higher distention pressures, all patients with a pouch referred sensations to the abdomen, as opposed to only one of nine controls with such a referral pattern (p < 0.0001). Pouch compliance was markedly reduced during study 1 but normalized after continuity was established with the proximal ileum. Anal sphincter function in patients with a pouch was similar to that in controls. CONCLUSIONS: Afferent pathways from both the ileum and rectum play a role in the mediation of sensations during mechanical distention of the ileoanal pouch and can explain a number of clinical features of patients with a pouch. The thresholds for activation of these pathways are not significantly altered by long-standing colorectal inflammation or by creation of the ileoanal pouch. Continuity with the proximal ileum significantly influences pouch compliance.

Rectal afferent function in patients with inflammatory and functional intestinal disorders.

Chronic symptoms of abdominal pain and discomfort are reported by patients with inflammatory bowel disease (IBD) and functional disorders of the gut, such as Irritable Bowel Syndrome (IBS). It has recently been suggested that transient inflammatory mucosal events may result in long-lasting sensitization of visceral afferent pathways. To determine the effect of recurring intestinal tissue irritation on lumbosacral afferent pathways, and to identify a plausible mechanism that could account for the overlap in symptomatology between IBD and IBS, we compared rectal afferent mechanisms in patients with Crohn's disease (inflammation limited to the ileum) with those observed in patients with diarrhea-predominant IBS. Continuous volume ramp and phasic pressure step distension of a rectal balloon were performed in 9 healthy male control subjects, 12 male patients with isolated ileal Crohn's disease and 9 male patients with diarrhea-predominant IBS using an electronic visceral stimulation device. The response of rectal afferents to distension was evaluated by measuring thresholds for the perception of physiological (stool) and aversive (discomfort) sensations, viscerosomatic referral patterns, skin conductance responses, receptive relaxation, and rectoanal reflex responses. In response to slow ramp distension, thresholds for aversive sensations were significantly higher in Crohn's disease patients, but similar between the two other groups. In response to rapid phasic distension, IBS patients reported discomfort at lower distension pressures, while all other thresholds were similar between groups. Skin conductance responses to aversive distension were greatly reduced in Crohn's disease patients while IBS patients had greater responses when compared to normals. Changes in viscerosomatic referral patterns and receptive relaxation rate were similar in Crohn's disease and IBS patients. These findings demonstrate that chronic ileal inflammation is associated with increased thresholds for discomfort and greatly diminished systemic autonomic reflex responses. In contrast, IBS patients show lowered thresholds for discomfort associated with increased autonomic responses. The findings in Crohn's patients may result from descending bulbospinal inhibition of sacral dorsal horn neurons in response to chronic intestinal tissue irritation.

Symptom duration in patients with irritable bowel syndrome.

OBJECTIVES: The etiology and natural history of irritable bowel syndrome (IBS) is poorly understood. We compared rectal sensory thresholds and compliance, SCL-90 scores, and follow-up questionnaires among normal controls, patients with longstanding ( > 5 y) disease (L-IBS), and patients with recent onset ( > 2 y) disease (R-IBS). The onset of symptoms in R-IBS was related to specific events such as infection (n = 10), surgery (n = 5), and stress (n = 4), but no specific event could be identified in six patients. METHODS: A diagnosis of IBS was made using Manning criteria ( > or = 3) and clinical grounds. Psychological data were obtained by psychometrics (SCL-90) scores. Rectal wall compliance and thresholds for the sensation of stool and discomfort were evaluated using the electronic barostat. RESULTS: The mean thresholds for phasic and ramp distention were similar for R-IBS and L-IBS groups for the perception of stool and discomfort. When compared with normals, the mean stool thresholds for phasic distention were significantly lower for L-IBS and R-IBS groups. SCL-90 scores were significantly increased in L-IBS in the mean phobia score (45 R-IBS vs 61 L-IBS), anxiety score (49 R-IBS vs 63 L-IBS), paranoia score (44 R-IBS vs 60 L-IBS), and hostility score (47 R-IBS vs 61 L-IBS) (all p < 0.05). On follow-up questionnaire, 60% of R-IBS versus 46% of L-IBS patients indicated that their symptoms had improved (p < 0.05). R-IBS patients also experienced fewer episodes of abdominal pain per week at follow-up than L-IBS patients (3.9 +/- 1.0 vs 8.5 +/- 1.7, respectively) (p < 0.05). CONCLUSIONS: Our findings suggest that IBS patients with short symptom duration and fewer psychological symptoms have a better prognosis than patients with a long history of IBS and associated psychological distress, although long term prospective studies are needed.

Effects of the corticotropin-releasing factor (CRF) on rectal afferent nerves in humans.

Corticotropin-releasing factor (CRF) released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may play a role in the modulation of rectal afferent function. In the current study we evaluated the effects of peripherally administered CRF on afferent mechanisms in the human rectum. We used rectal balloon distention in seven healthy volunteers to evaluate the effect of CRF (1 microgram/kg) on visceral afferents originating in the rectum which are involved in the following functions: thresholds and intensity of conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum using a volume ramp (40 and 400 mL/min), or by intermittent phasic distention. CRF decreased the thresholds and increased the intensity for the sensation of discomfort in response to both ramp and phasic distention. During slow ramp distention, CRF also lowered the stool threshold. CRF increased rectal compliance during slow ramp distention without affecting the rate of receptive relaxation or the inflection point of the compliance curve. CRF had no effect on viscerosomatic referral patterns, or on the rectoanal inhibitory reflex. These findings are consistent with a dual effect of CRF on afferent pathways mediating perception of aversive rectal sensations, and on rectal smooth muscle.