A Placebo-Controlled Trial of Itopride in Dyspepsia

Abstract & Commentary

By Malcolm Robinson, MD, FACP, FACG, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson serves as a consultant for TAP, Pfizer, Janssen, Eisai, J&J-Merck, and Procter & Gamble, is on the speaker's bureau of Janssen, Eli Lilly, Solvay, TAP, and Aventis, and does research for Forest Labs, Wyeth-Ayerst, AstraZeneca, and Centocor.

Source: Holtmann G, et al. A placebo-controlled trial of itopride in functional dyspepsia. N Engl J Med. 2006;354:832-840.

Synopsis: Itopride, a D2 dopamine agonist with anticholinesterase effects, was marginally superior to placebo in 'functional dyspepsia.'

In this study, 523 patients with chronic unexplained upper abdominal pain received 50, 100, or 200 mg of itopride or placebo t.i.d. for 8 weeks. At the end of the study, 41 percent of placebo recipients were symptom free compared to 57 percent, 59 percent, and 64 percent of the respective itopride recipients. Analysis of combined pain and fullness demonstrated 73 percent response with itopride vs 63 percent with placebo. Past studies of patients with functional dyspepsia have shown only small benefits vs placebo for histamine H2 receptor antagonists, proton pump inhibitors (PPIs), and Helicobacter pylori eradication. Itopride is currently widely used in Japan in the 50 mg t.i.d. dose, but reliable studies were felt to be lacking by the current investigators. Symptoms acceptable for the diagnosis of functional dyspepsia (FD) were: persistent or recurrent (at least 12 weeks during the past year) abdominal pain or discomfort. Discomfort could include early satiety, postprandial fullness, bloating, and nausea. Symptoms strongly suggesting gastroesophageal reflux disease (GERD) as the major diagnosis made patients ineligible, but some patients had concomitant GERD symptoms. Study sites were in Germany. Eight dyspepsia symptoms were assessed using a questionnaire with 6 grades for each symptom. Quality of life was monitored along with compliance and safety. The study was funded by the sponsor (Knoll, Germany).

Complex statistics were used, and the authors concluded that there were significant differences overall between active drug (all doses) and placebo. However, there were no statistical differences between the various doses. The authors also state that only 6 patients would have to be treated for one patient to achieve either marked or complete improvement. This compares with 9 patients needed to treat for similar benefit from a PPI used in FD. Itopride is thought to exercise prokinetic effects via its antidopaminergic and antiacetylcholinesterase actions. Adverse effects did not appear to differ between placebo and itopride. The most common adverse effects were abdominal pain, nausea, diarrhea, and constipation. Prolactin levels were elevated in the recipients of itopride, particularly the higher doses. The authors certainly admitted that there would be a need for further studies to determine the ideal itopride dose and to document its precise mode of action.

Commentary

A helpful editorial accompanied this article.1 The editorial stressed the strong input of psychological factors to the pathogenesis of FD, the difficulty of differentiating these patients from those with more ominous organic disease, and the disastrous consequences of such therapeutic approaches to FD as empirical cholecystectomy (including cholecystectomy for impaired scintigraphic gallbladder emptying). Endoscopy is seldom helpful for FD patients. At least in most North American populations, H. pylori eradication is likely to be useless (at best, helping one patient for every 15 eradications). Overall, despite the authors' claims, the itopride study strikes me as very underwhelming.

Functional dyspepsia is likely to be a mélange of different disorders, all with diverging pathophysiologies and few likely to respond well to any pharmacologic treatment. Until we can diagnostically separate the patients with primary motor disorders from those with primary sensory disorders from those with entirely psychiatric underpinnings for their symptoms, there will be no magic bullet. Itopride sounds to me like a new metoclopramide or cisapride, possibly (but not certainly) less risky than these agents. However, I sincerely doubt that we will be itopride enthusiasts a decade from now. We must do better for these difficult and ubiquitous patients.

Reference

1. Longstreth G, et al. Functional dyspepsia—managing the conundrum. N Engl J Med. 354;8:791-793.