title: Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug-Induced Small Bowel Injury: A Randomized, Placebo-Controlled Trial.
abstract: Some studies have reported a high incidence of small bowel injuries in 60%-80% of subjects who take nonselective nonsteroidal anti-inflammatory drugs and PPIs simultaneously. We performed a randomized, double-blind, controlled study to determine whether proton pump inhibitors (PPIs) exacerbate nonsteroidal anti-inflammatory drug-induced small bowel injury.
  
  
  
  Fifty-seven healthy subjects were randomly assigned groups given the cyclooxygenase (COX) 2 inhibitor celecoxib (200 mg, twice daily) plus placebo for 2 weeks (COX-2 + placebo group, n = 30), or celecoxib plus the PPI rabeprazole (20 mg, once daily) for 2 weeks (COX-2 + PPI group, n = 27). The study was performed from October 2012 through September 2013 at a tertiary medical center in Japan. All subjects were evaluated by capsule endoscopy at the start of the study and then after 2 weeks administration of celecoxib with rabeprazole or placebo. The incidence rates and the numbers of small bowel injuries (ulcers and erosions) that were observed under capsule endoscopy were compared between groups. The primary endpoint was the incidence of mucosal injuries at the second capsule endoscopy examination.
  
  
  
  A significantly higher proportion of subjects in the COX-2 + PPI group developed small bowel injury (12 of 27 subjects; 44.4%) than in the COX-2 + placebo group (5 of 30 subjects; 16.7%; P = .04). Subjects in the COX-2 + PPI group had a significant increase in risk of small bowel injury compared with the COX-2 + placebo group (relative risk, 2.67; 95% confidence interval, 1.08-6.58). The number of erosions in each member of the COX-2 + PPI group was greater than in each member of the COX-2 + placebo group (P = .02). The number of ulcers did not differ between groups. Twenty-six percent of subjects in the COX-2 + PPI group developed mucosal injury in the jejunum, compared with none of the subjects in the COX-2 + placebo group (P = .003); no such trend was found in the ileum.
  
  
  
  In a randomized, controlled trial, PPIs increased the risk of short-term nonsteroidal anti-inflammatory drug-induced small bowel injury. UMIN clinical trial registry number: UMIN000008883.
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ema
authors.initials: E
authors.lastname: Washio
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Esaki
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Maehata
authors.affiliation: Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ishikawa
authors.affiliation: Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan. Electronic address: tmatsumo@iwate-med.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects*; D053704:Capsule Endoscopy; D000068579:Celecoxib / Q000008:administration & dosage / Q000009:adverse effects; D004311:Double-Blind Method; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D015994:Incidence; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000453:epidemiology* / Q000473:pathology; D007413:Intestinal Mucosa / Q000473:pathology; D007564:Japan / Q000453:epidemiology; D008297:Male; D010919:Placebos / Q000008:administration & dosage; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects*; D064750:Rabeprazole / Q000008:administration & dosage / Q000009:adverse effects; D062606:Tertiary Care Centers
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010919:Placebos; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D000068579:Celecoxib
keywords: COX-2; Cyclooxygenase-2 Inhibitor; Damage; Intestine