title: Does co-administration of a non-selective opiate antagonist enhance acceleration of transit by a 5-HT4 agonist in constipation-predominant irritable bowel syndrome? A randomized controlled trial.
abstract: Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. foxx-orenstein.amy@mayo.edu
authors.forename: A E
authors.initials: AE
authors.lastname: Foxx-Orenstein
authors.forename: M
authors.initials: M
authors.lastname: Camilleri
authors.forename: L A
authors.initials: LA
authors.lastname: Szarka
authors.forename: S
authors.initials: S
authors.lastname: McKinzie
authors.forename: D
authors.initials: D
authors.lastname: Burton
authors.forename: G
authors.initials: G
authors.lastname: Thomforde
authors.forename: K
authors.initials: K
authors.lastname: Baxter
authors.forename: A R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D003248:Constipation / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage*
chemical_list: D007211:Indoles; D009292:Narcotic Antagonists; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C105050:tegaserod; D009271:Naltrexone