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.

Possible role of nitric oxide in visceral hypersensitivity in patients with irritable bowel syndrome.

BACKGROUND: Visceral hypersensitivity is a consistent finding in a considerable proportion of patients with irritable bowel syndrome (IBS), and may provide a physiological basis for the development of IBS symptoms. In this study, we aimed to confirm the hypothesis that nitric oxide (NO) is involved in maintaining visceral hypersensitivity in IBS. Ten healthy volunteers (HV) and 12 IBS patients with documented hypersensitivity to rectal distension underwent a rectal barostat study. The effect of placebo and the specific NO synthase inhibitor NG -monomethyl-L-arginine (L-NMMA) on resting volume, rectal sensitivity to distension and rectal compliance was evaluated in a double-blind, randomized, cross-over fashion. NG -monomethyl-L-arginine did not alter resting volumes in HV or IBS patients. In HV, l-NMMA did not alter rectal sensory thresholds compared to placebo (45 +/- 3 and 46 +/- 3 mmHg, respectively). In contrast, L-NMMA significantly increased the threshold for discomfort/pain in IBS patients (placebo: 18 +/- 2, l-NMMA: 21 +/- 3 mmHg, P < 0.05). Rectal compliance was not affected by L-NMMA. Although NO does not seem to play a major role in normal rectal sensation or tone, we provide evidence that NO may be involved in the pathophysiology of visceral hypersensitivity in IBS.

The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients.

BACKGROUND: Visceral hypersensitivity to distension is thought to play an important role in the pathophysiology of the irritable bowel syndrome (IBS). Cannabinoids are known to decrease somatic pain perception, but their effect on visceral sensitivity in IBS remains unclear. Therefore, we evaluated the effect of the mixed CB(1) /CB(2) receptor agonist delta-9-tetrahydrocannabinol (Δ(9) -THC, dronabinol) on rectal sensitivity. METHODS: Ten IBS patients and 12 healthy volunteers (HV) underwent a barostat study to assess rectal sensitivity using an intermittent pressure-controlled distension protocol before and after sigmoid stimulation. Repetitive sigmoid stimulation is a validated method to increase visceral perception in IBS patients, consisting of a 10-min period of 30 s stimuli (60 mmHg), separated by 30 s of rest (5 mmHg). The effect of placebo and Δ(9) -THC (5 and 10 mg in healthy volunteers and 10 mg in IBS patients) on rectal sensitivity was evaluated on respectively three and two separate days in a double blind, randomized, crossover fashion. KEY RESULTS: All participants (HV and IBS) reported central side effects during the highest dose of Δ(9) -THC, most frequently increased awareness of the surrounding, light-headedness and sleepiness, whereas no side effects where reported during placebo. Although blood pressure was not affected, heart rate increased in both HV and IBS, but was most pronounced in IBS patients. The cannabinoid agonist Δ(9) -THC did not alter baseline rectal perception to distension compared to placebo in HV or IBS patients. Similarly, after sigmoid stimulation there were no significant differences between placebo and Δ(9) -THC in sensory thresholds of discomfort. CONCLUSIONS & INFERENCES: These findings imply that Δ(9) -THC does not modify visceral perception to rectal distension and argue against (centrally acting) CB agonists as tool to decrease visceral hypersensitivity in IBS patients.

Randomised clinical trial: the effects of amitriptyline on drinking capacity and symptoms in patients with functional dyspepsia, a double-blind placebo-controlled study.

BACKGROUND: Functional dyspepsia is one of the most prevalent (15-40%) functional gastrointestinal disorders. Antidepressants such as amitriptyline are often used in these patients, but clinical studies are currently lacking. AIM: To evaluate the effect of 8 weeks of treatment with amitriptyline on drinking capacity, symptoms evoked by a standardised drink test (primary endpoint) and clinical symptoms (secondary endpoint). METHODS: Patients meeting the Rome III criteria for functional dyspepsia (FD) were invited to participate in a double blind, randomised, placebo-controlled trial and were treated with either amitriptyline (12.5-50 mg) or placebo during 8 weeks. All included patients underwent a nutrient drink test before and after treatment. Drinking capacity and evoked symptoms were recorded. In addition, dyspeptic symptoms were weekly assessed using PAGI SYM (patient assessment of upper gastrointestinal symptom severity index) questionnaire. RESULTS: Thirty-eight patients (amitriptyline n=18, placebo n=20; age 41±2year, 61% F) completed the study. The drinking capacity of liquid meal was not affected by either amitriptyline or placebo treatment. Postprandial symptoms were not significantly different between amitriptyline and placebo. During the entire treatment, total symptom score (0.47 points, P=0.02) and nausea (0.86 points, P=0.004) on PAGI SYM were significantly reduced by amitriptyline compared with placebo. CONCLUSIONS: Amitriptyline did not affect drinking capacity and postprandial symptoms evoked by the drink test in FD patients. However, total clinical symptom score and nausea were reduced during 8 weeks of treatment. Our data suggest that amitriptyline particularly improves nausea in functional dyspepsia, but larger clinical trials are needed to further confirm our findings.

Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated rats.

Irritable bowel syndrome is in part characterized by an increased sensitivity to colonic distension. Stress is an important trigger factor for symptom generation. We hypothesized that stress induces visceral hypersensitivity via mast cell degranulation and transient receptor ion channel 1 (TRPV1) modulation. We used the rat model of neonatal maternal separation (MS) to investigate this hypothesis. The visceromotor response to colonic distention was assessed in adult MS and non-handled (NH) rats before and after acute water avoidance (WA) stress. We evaluated the effect of the mast cell stabilizer doxantrazole, neutralizing antiserum against the mast cell mediator nerve growth factor (NGF) and two different TRPV1 antagonists; capsazepine (non-specific) and SB-705498 (TRPV1-specific). Immunohistochemistry was used to assess post-WA TRPV1 expression in dorsal root ganglia and the presence of immunocytes in proximal and distal colon. Retrograde labelled and microdissected dorsal root ganglia sensory neurons were used to evaluate TRPV1 gene transcription. Results showed that acute stress induces colonic hypersensitivity in MS but not in NH rats. Hypersensitivity was prevented by prestress administration of doxantrazole and anti-NGF. Capsazepine inhibited and SB-705498 reversed poststress hypersensitivity. In MS rats, acute stress induced a slight increase in colonic mast cell numbers without further signs of inflammation. Post-WA TRPV1 transcription and expression was not higher in MS than NH rats. In conclusion, the present data on stress-induced visceral hypersensitivity confirm earlier reports on the essential role of mast cells and NGF. Moreover, the results also suggest that TRPV1 modulation (in the absence of overt inflammation) is involved in this response. Thus, mast cells and TRPV1 are potential targets to treat stress-induced visceral hypersensitivity.