Abstract: We identified 25 RCTs from 27 papers (with 8453 participants) studying the effect of PPIs versus placebo, H2RAs or prokinetics for improvement of global symptoms of dyspepsia and quality of life in people with FD. Low-dose PPIs had similar efficacy as standard-dose PPIs, therefore we combined these subgroups for the analysis. PPI was more effective than placebo at relieving overall dyspepsia symptoms in people with FD (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.94; participants = 6172; studies = 18; number needed to treat for an additional beneficial outcome (NNTB) 11; moderate quality evidence). PPIs may have little or no effect compared with H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2; low quality evidence), and may be slightly more effective than prokinetics (RR 0.89, 95% CI 0.81 to 0.99; participants = 1033; studies = 5; NNTB 16; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics have probably little or no effect compared with PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; moderate quality evidence). There was no difference when subgrouped by Helicobacter pylori status, country of origin, or presence of reflux or Rome III subtypes. There were no differences in the number of adverse events observed between PPIs and any of the other treatments. There were fewer adverse events in the combination of PPI plus prokinetics compared to prokinetics alone (RR 0.60, 95% CI 0.39 to 0.93; participants = 407; studies = 2; moderate quality evidence). There is evidence that PPIs are effective for the treatment of FD, independent of the dose and duration of treatment compared with placebo. PPIs may be slightly more effective than prokinetics for the treatment of FD; however, the evidence is scarce. The trials evaluating PPIs versus prokinetics are difficult to interpret as they are at risk of bias. Although the effect of these drugs seems to be small, the drugs are well tolerated.

Plain-language summary: We included 25 studies (with 8453 participants). There were six studies (2304 participants) comparing low-dose PPIs versus standard-dose PPIs (the dose used in clinical practice); 18 studies (6172 participants) comparing PPIs with placebo (pretend treatment); two studies (740 participants) comparing PPIs with H2RAs; five studies (1033 participants) comparing PPIs with prokinetics and two studies (407 participants) comparing PPIs plus prokinetics versus prokinetics alone. The duration of the treatment lasted at least two weeks. Seven studies reported treatment for two weeks, 12 studies reported treatment for four weeks and five studies reported more than six weeks of treatment. The treatment period was unclear in one study. Seventeen of the 25 studies were sponsored or funded by a pharmaceutical company and two by an institution grant. There was no information on funding in eight studies. Our review showed that PPIs are more effective than placebo, and are probably slightly more effective than prokinetics for the treatment of functional dyspepsia. Low-dose and standard-dose PPIs were similarly effective on the relief of indigestion, so we combined the results of the two doses of PPI. PPI was more effective than placebo, with 31% of the PPI group reporting no or minimal symptoms compared with 26% of the placebo group. The effect of PPI was probably slightly more effective than H2RAs; however, the two studies involved in the analysis were so different that it may have influenced the results. There was no difference in the number of reported side effects when comparing PPIs, H2RAs and prokinetics. The studies evaluating the effect of PPIs compared to placebo or PPIs combined with prokinetics versus prokinetics were in general of good quality. However, the studies that compared PPIs versus H2RAs and prokinetics had serious quality issues.