How effective are medicines that suppress stomach acid for the treatment of indigestion in adults with no other major disease?
Acid suppression is a possible treatment for functional dyspepsia (indigestion), which is recurring pain over the stomach, bloating, burping or the feeling of being full. Several medicines are used to treat functional dyspepsia; proton pump inhibitors (PPIs) and H2 receptor antagonists (H2RAs) reduce stomach acid, and prokinetics accelerate stomach emptying. There is no clear evidence that one medicine is more effective than another. Although these are considered safe, a few people have side effects. The most common side effects are headache, tummy (abdominal) pain, bloating, diarrhoea and feeling sick (nausea). Long-term use of PPIs has been associated with infectious diarrhoea (inflammation of the stomach and small intestine), bone fracture and bacterial overgrowth. Therefore, we need to know whether these medications are effective and safe for people with indigestion.
We searched medical databases for clinical trials in which treatment was allocated by chance (called randomized controlled trials) in adults with functional dyspepsia up to February 2016. We included results from 23 studies from 22 publications. We found one ongoing study and one study that is awaiting further details.
We included 23 studies (with 8759 participants). There were six studies (2304 participants) comparing low-dose PPIs versus standard-dose PPIs (the dose used in clinical practice); 16 studies (5968 participants) comparing PPIs with placebo (pretend treatment); two studies (740 participants) comparing PPIs with H2RAs; four studies (892 participants) comparing PPIs with prokinetics and two studies (407 participants) comparing PPIs plus prokinetics versus prokinetics alone.
The duration of the treatment lasted from two to eight weeks. Seven studies reported treatment for two weeks; 11 studies reported treatment for four weeks and five studies reported eight weeks of treatment.
Study funding sources
Fifteen of the 23 studies were sponsored or funded by a pharmaceutical company and one by an institution grant. There was no information on funding in seven studies.
Our review showed that PPIs are more effective than placebo, and are probably slightly more effective than H2RAs and 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 30% of the PPI group reporting no or minimal symptoms compared with 25% 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. PPI was slightly more effective than prokinetics. There was no difference in the number of reported side effects when comparing PPIs, H2RAs and prokinetics.
Quality of the evidence
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.
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 H2RAs 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.
Functional dyspepsia (FD or non-ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD.
To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia.
We searched in the following electronic databases: the Cochrane Library (to January 2016), MEDLINE (OvidSP; to February 2016), Embase (OvidSP; to February 2016), and SIGLE grey literature (up to February 2016) and clinical trial registries; we handsearched abstracts from conferences up to February 2016. We screened non-systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information.
All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group).
Two review authors independently assessed eligibility, trial quality and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events were beyond the scope of this review.
We identified 23 RCTs from 22 papers (with 8759 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. Two to eight weeks of therapy with PPI was slightly 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 = 5968; studies = 16; number needed to treat for an additional beneficial outcome (NNTB) 13; moderate quality evidence). PPIs may be slightly more effective than H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2, NNTB 13; low quality evidence), and slightly more effective than prokinetics (RR 0.90, 95% CI 0.81 to 1.00; participants = 892; studies = 4; NNTB 20; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics were possibly slightly more effective than PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; NNTB 18; moderate quality evidence).
The 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.