The pathogenesis of FD is far from fully understood, but gastrointestinal motility and visceral sensitivity are proven to play very important roles[21,22
] in the occurrence of FD symptoms. Clinically, prokinetic agents, such as domperidone, cisapride, and mosapride, are often used to treat these patients. Recently a meta-analysis by Hiyama[23
] showed a significant treatment benefit in favour of prokinetic agents in patients with FD. However, in that study, itopride is rarely involved. Given the concern for safety and efficacy of the existing prokinetic agents, a novel agent that is safer and more effective is urgently needed. Itopride is a prokinetic agent that has a completely different mechanism of action from existing ones; it works by both antagonizing dopamine receptors and inhibiting the activity of acetylcholinesterase. It not only stimulates release of acetylcholine, but also inhibits its degradation, thus promoting gastrointestinal motility. There are a few well-designed RCTs on the efficacy of itopride in the treatment of FD, and the reported efficacy was controversial. Therefore, a meta-analysis of previously published high quality RCTs was conducted.
In the present study, when compared with the control groups, the RRs of itopride for GPA, postprandial fullness, and early satiation of FD patients indicate that this drug could significantly improve the GPA scores, postprandial fullness, and early satiation in FD patients. However, it did not improve epigastric discomfort more significantly than the comparator, which could be a result of itopride’s action of increasing postprandial gastric receptive relaxation[24
] and gastrointestinal motility[20
]. To further evaluate the efficacy of itopride in improving the symptoms of FD patients, the LDQ was used to evaluate FD patients’ symptoms at baseline and after treatment, and the calculated WMD was -1.38 [95%CI: (-1.75, -1.01), P
< 0.01], suggesting that the drug could significantly reduce the LDQ scores of FD patients, which made the results more convincing. As for safety, it showed that the incidence of ADRs was no higher for itopride than for domperidone, mosapride, or placebo. The ADRs attributed to itopride were mainly abdominal pain and diarrhoea, which were all mild to moderate, without clinically related changes in the electrocardiogram, particularly prolongation of QT intervals. This appears to be different from other prokinetic agents, possibly because the polarity of itopride largely prevents it from entering the brain or the CNS[25
]. In addition, as compared with other dopamine receptor antagonists, itopride caused a much lower incidence of CNS-related ADRs and hyperprolactinaemia while keeping dopamine active. Meanwhile, there were fewer drug interactions of itopride compared with other prokinetic agents[26
], probably because itopride is metabolized by a monooxygenase, while mosapride and other prokinetics are metabolized by cytochrome P450, as reported by Mushiroda[26
Considering the discrepancy in contradictory trial results[12,20
], study design issues are important. There were several probable reasons, including heterogeneity of the conditions and differences in patient selection. In the Tally’s trial, the requirement that all patients had to be H. pylori
negative, exclusion of heartburn and that the LDQ score needed to be > 9 at baseline meant high intensity scores for the typical symptoms of pain and fullness were needed for LDQ, all of which might contribute to the high placebo response rate[12
]. On the other hand, the majority of dyspeptic subjects overlap with heartburn symptoms as well as H. pylori
infection, and heartburn also is a predictor of response, so the exclusion criteria were much stricter in the Tally’s study, as Veldhuyzen mentioned[27
This meta-analysis covered a wide range of high-quality articles, and all studies included were randomized controlled trials RCTs. In addition, the diagnostic criteria for inclusion of articles were uniform. Considering publication bias, that is, the disproportionate publication of research articles with a positive result than of those with a negative result, an effort was made to collect as full a range of related literature as possible through many different approaches (including computer search, manual search, and literature tracing), and repeated publications were excluded. All nine studies included in this analysis had definitive inclusion criteria and baseline descriptions of sex, age, disease severity, and concomitant medications of the population included, and the ratios of the population in the study groups and the control groups were reasonable.
However, the present study did have some limitations. Firstly, the ethnic groups of the populations in the articles were varied. Race and/or western lifestyle are important risk factors[28,29
]. Secondly, because of differences in trial design, comparators used for the control group, and follow-up, there was a large degree of heterogeneity among the studies included, as well as in the GPA, early satiation, and LDQ scores. For this reason, a random effect model was used for the meta-analysis, which probably affected the results of the evaluation. Thirdly, Helicobacter pylori may play a role in pathogenesis of functional dyspepsia[1
]. However, seven of the FD trials included in this meta-analysis were from Asia, which has a higher prevalence of Hp, and this probably affected the results.
In summary, the results of this meta-analysis suggest that itopride has therapeutic benefits with respect to GPA, postprandial fullness, early satiation, and the LDQ of FD patients, with a lower incidence of ADRs. However, because of the existence of heterogeneity, further studies of more high-quality RCTs with consistent indicators are probably warranted to validate the safety and efficacy of itopride.