AIM: To compare efficacy of proton pump inhibitors (PPIs) with H₂-receptor antagonists (H₂RAs) plus prokinetics (Proks) for dysmotility-like symptoms in functional dyspepsia (FD).

METHODS: Subjects were randomized to receive open-label treatment with either rabeprazole 10 mg od (n = 57) or famotidine 10 mg bid plus mosapride 5 mg tid (n = 57) for 4 wk. The primary efficacy endpoint was change (%) from baseline in total dysmotility-like dyspepsia symptom score. The secondary efficacy endpoint was patient satisfaction with treatment.

RESULTS: The improvement in dysmotility-like dyspepsia symptom score on day 28 was significantly greater in the rabeprazole group (22.5% ± 29.2% of baseline) than the famotidine + mosapride group (53.2% ± 58.6% of baseline, P < 0.0001). The superior benefit of rabeprazole treatment after 28 d was consistent regardless of Helicobacter pylori status. Significantly more subjects in the rabeprazole group were satisfied or very satisfied with treatment on day 28 than in the famotidine + mosapride group (87.7% vs 59.6%, P = 0.0012). Rabeprazole therapy was the only significant predictor of treatment response (P < 0.0001), defined as a total symptom score improvement ≥ 50%.

CONCLUSION: PPI monotherapy improves dysmotility-like symptoms significantly better than H₂RAs plus Proks, and should be the treatment of first choice for Japanese FD.

Functional dyspepsia (FD) is a condition characterized by persistent upper abdominal symptoms in the absence of any causative organic disease[1]. It is thought to be caused by a combination of different factors, including dysmotility or hypersensitivity of the gastrointestinal (GI) tract, gastric acid secretion, inflammation of the gastric mucosa, altered sympathetic or parasympathetic activity, altered secretion of GI hormones, and psychological factors[2,3]. Treatments vary according to the symptoms, and include gastroprokinetic agents, suppressors of gastric acid secretion, antidepressants, anxiolytics and Chinese herbal medicines. Although it has been shown that gastric acid secretion is normal in patients with FD[4], a subset of these patients will benefit from strong acid suppression by a proton pump inhibitor (PPI)[5]. Inhibitors of acid secretion are therefore widely prescribed to patients with FD worldwide. Although treatment with acid suppression produces symptom relief in a proportion of patients with FD, this effect has not been reported consistently in all studies[6-8]. A Japanese study surveyed the prescribing habits of primary care physicians for functional GI symptoms and evaluated the efficacy and indications of the medications prescribed[9]. It was found that H₂-receptor antagonists (H₂RAs) are the treatment of first choice for ulcer-like symptoms such as epigastric pain, and prokinetics (Proks) for dysmotility-like symptoms such as epigastric discomfort, heaviness, and bloating. In other words, Japanese primary care physicians prefer H₂RA + prokinetic combination therapy for FD symptoms.

For FD patients with at least mild heartburn and/or regurgitation at baseline, omeprazole is associated with higher treatment success rates at 4 wk than ranitidine, cisapride and placebo[10]. In those patients who have either no or minimal heartburn and/or regurgitation at baseline, omeprazole and ranitidine are superior to placebo, although no significant difference is seen between omeprazole and ranitidine[10]. The question of whether more effective acid suppression is efficacious in Japanese patients with FD has yet to be adequately tested.

It is reasonable to think that H₂RAs provide adequate relief for FD symptoms in Japanese patients, who have a higher rate of Helicobacter pylori (H. pylori) infection than their western counterparts, as well as lower levels of gastric acid secretion[11].

Complete relief of symptoms is significantly more common with omeprazole than with placebo in subgroups of patients with ulcer-like and reflux-like dyspepsia, whereas, as might be expected, there is no indication of benefit with omeprazole in patients with dysmotility-like dyspepsia[5]. In addition, meta-analyses suggest that H₂RA and Proks are superior to placebo in non-ulcer dyspepsia (NUD)[12,13].

In this study, we concentrated on dysmotility-like symptoms in patients with FD, and compared the efficacy of PPI monotherapy and combination therapy with H₂RAs and Proks, which is widely prescribed by Japanese primary care physicians for FD symptoms.

A total of 146 patients were randomized. Thirty-two patients were excluded in the follow-up period (30 lost to follow-up, two for non-compliance), leaving 114 patients for inclusion in the analysis. Fifty-seven patients were randomized to receive PPI treatment, and 57 to receive H₂RA + Prok treatment (Figure 1). Baseline demographic characteristics and symptom scores of the patients who completed the treatment period are given in Table 1. There were no significant differences between the characteristics of the two treatment groups at baseline.

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Figure 1 Study flow chart. This study enrolled 146 subjects with functional dyspepsia and, after excluding 30 subjects for non-attendance and two for non-compliance, 57 subjects in each treatment group completed the study.

Change in dysmotility-like dyspepsia symptom score

No significant differences were seen between groups in the change in dysmotility-like dyspepsia symptom score from baseline to 3 d or 7 d of treatment. After 28 d of treatment, the change in symptom score was significantly greater in the PPI group (22.5% ± 29.2% of baseline) than in the H₂RA + Prok group (53.2% ± 58.6% of baseline) (P < 0.0001), indicating greater improvement in symptoms with PPI treatment (Figure 2). A significant improvement in total symptom score was seen over time in both groups, but in the H₂RA + Prok group, the improvements in total symptom score on days 14 and 28 were not significantly greater than at day 7, whereas in the PPI group, the improvements in total symptom score at day 14 (38.4% ± 37.8% of baseline, P = 0.0034) and day 28 (P < 0.0001) were both significantly greater than on day 7 (45.1% ± 33.8% of baseline) (Figure 2).

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Figure 2 Change in dysmotility-like dyspepsia symptom score over time. Significantly greater improvement was seen in dysmotility-like dyspepsia symptom score on day 28 of treatment in the proton pump inhibitor (PPI) group than in the H₂-receptor antagonist (H₂RA) + prokinetic (Prok) group. No significant additional symptomatic improvement was seen after day 7 of H₂RA + Prok treatment, whereas further symptomatic improvements were seen over time in the PPI group. ^aP < 0.05, PPI vs H₂RA + Prok; ^cP < 0.05 vs pre-Rx in each group; ^eP < 0.05 vs 7 d Rx in each group.

Change in dysmotility-like dyspepsia symptom score according to H. pylori status

Among H. pylori-positive subjects, a significantly greater improvement in total symptom score was seen in the PPI group (13.4% ± 26.2% of baseline) than in the H₂RA + Prok group (53.4% ± 34.7% of baseline) (P < 0.007) by the end of the treatment period. Significant symptomatic improvement was seen over time in both treatment groups, although in the H₂RA + Prok group, no further improvement was observed after day 7 (35.7% ± 31.6% of baseline). In the PPI group, there was no significant difference between the changes in total symptom score for days 7 and 14, although there was a statistically significant difference between days 7 and 28 (P = 0.0277) (Figure 3A).

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Figure 3 Change in dysmotility-like dyspepsia symptom score over time according to Helicobacter pylori status. Significantly greater symptomatic improvement was seen in the proton pump inhibitor group than in the H₂-receptor antagonist (H₂RA) + prokinetic (Prok) group after 28 d of treatment, regardless of Helicobacter pylori (H. pylori) status. No additional significant symptomatic improvement was seen after day 7 of H₂RA + Prok treatment, regardless of H. pylori status. ^aP < 0.05, PPI vs H₂RA + Prok; ^cP < 0.05 vs pre-Rx in each group; ^eP < 0.05 vs 7 d Rx in each group.

Among H. pylori-negative subjects, a significantly greater improvement in total symptom score was seen in the PPI group (24.1% ± 31.7% of baseline) than in the H₂RA + Prok group (53.1% ± 72.2% of baseline, P < 0.0001) on day 28. Significant symptomatic improvement was seen over time in both treatment groups, although the improvements seen in the H₂RA + Prok group on days 14 and 28 were not significantly superior to those observed on day 7. In the PPI group, the reductions in total symptom score on days 14 (44.2% ± 42.0% of baseline, P = 0.0177) and 28 (P = 0.0002) were both significantly greater than on day 7 (52.4% ± 34.1% of baseline) (Figure 3B).

Subject satisfaction on days 14 and 28 of treatment

Although no significant difference was seen between the groups on day 14, the proportion of subjects who were satisfied or very satisfied with their treatment was significantly higher in the PPI group than in the H₂RA + Prok group on day 28 (87.7% vs 59.6%, P = 0.0012). No significant increase was seen in subject satisfaction in the H₂RA + Prok group between days 14 and 28, whereas a significant increase was seen in the proportion of subjects in the PPI group answering satisfied or very satisfied between day 14 (63.2%) and 28 (P = 0.0042) (Figure 4).

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Figure 4 Subject satisfaction after 14 d and 28 d of treatment. Subject satisfaction was significantly higher in the proton pump inhibitor (PPI) group than in the H₂-receptor antagonist (H₂RA) + prokinetic (Prok) group on day 28 of treatment. No significant increase in subject satisfaction was seen in the H₂RA + Prok group between days 14 and 28, whereas a significant increase was seen in the PPI group between days 14 and 28. ^aP < 0.05, PPI vs H₂RA + Prok; ^cP < 0.05 vs 14 d Rx.

The Rome III criteria define FD as “the chronic presence of one or more dyspepsia symptoms (bothersome postprandial fullness, early satiation, epigastric pain, epigastric burning) that are considered to originate from the gastroduodenal region, with no evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms”[1]. FD is a common condition[14,15], with considerable adverse impact on quality of life[16], and represents a serious problem in everyday clinical practice. Patients with FD present with a variety of symptoms[17,18], so based on the symptom profile, they may be prescribed gastroprokinetic agents, suppressors of gastric acid secretion, antidepressants, anxiolytics or Chinese herbal medicines[19]. A Japanese survey of the prescribing habits of primary care physicians for upper GI symptoms has found that H₂RAs are prescribed for epigastric pain and heartburn, and Proks for epigastric discomfort, nausea and loss of appetite[9]. In other words, H₂RAs rather than PPIs are prescribed for epigastric pain syndrome[1], characterized by the two symptoms of epigastric pain and epigastric burning, unrelated to meals and considered mainly related to gastric acid. Proks are widely prescribed for postprandial distress syndrome[1], characterized by the two symptoms of postprandial fullness and early satiation, and considered to be strongly related to dysmotility of the GI tract; in particular, gastric accommodation of adaptive relaxation. H₂RA + Prok combination therapy is widely prescribed in Japan, where dyspepsia is not a recognized diagnosis for insurance purposes.

It has recently become clear that gastric acid secretion is strongly associated with the onset of dysmotility-like symptoms. Lee et al[20] have examined the influence of acid on gastric hypersensitivity and motility in healthy subjects, and have found that duodenal acidification significantly induces gastric hypersensitivity and impairs gastric motility. Compared with saline, infusion of acid into the duodenum causes not only ulcer reflux symptoms such as heartburn, but also dysmotility-like symptoms such as epigastric discomfort, belching and abdominal bloating[20]. When Miwa et al[21] infused acid into the stomach of Japanese subjects, they induced a variety of dyspeptic symptoms, with no significant change in acid-reflux-related symptoms such as heartburn and epigastric pain, but a significant increase in dysmotility-like symptoms such as epigastric discomfort, stomach fullness, nausea and belching. Samsom et al[22] have reported that decreased acid clearance and increased sensitivity to acid in patients with dyspepsia may lead to dyspeptic symptoms. There have in fact been a number of recent studies reporting the effectiveness of PPIs[7] and H₂RAs[23] in the treatment of FD. Empirical omeprazole therapy induces symptom improvement in a higher proportion of patients with uninvestigated dyspepsia (defined as epigastric pain or discomfort with or without heartburn or regurgitation) than ranitidine or cisapride does, but this effect is more marked in patients with gastroesophageal reflux disease[10]. The prevalence of pathological pH monitoring (4%-6% of time at pH < 4) is significantly higher in FD patients with heartburn than those without[17]. In other words, PPIs are more effective than H₂RAs in the treatment of FD associated with heartburn and regurgitation.

It is unclear, however, how important suppression of acid secretion is in Japanese patients, who have a high prevalence of H. pylori infection and low levels of gastric acid secretion[11]. A Japanese clinical trial found that H₂RA therapy was more effective than mosapride for treatment of FD[24], suggesting that suppression of gastric acid secretion by an H₂RA may be sufficient to treat FD in Japanese patients, with no need for a PPI. In this study, we compared PPI monotherapy with H₂RA + Prok combination therapy; the therapy most commonly prescribed by Japanese clinicians[9]. In consideration of the superior acid secretion suppression of PPIs over H₂RAs, we combined an H₂RA with a Prok, and examined only dysmotility-like symptoms, considered less responsive to PPI therapy.

Our results showed no differences between treatment groups for changes in dysmotility-like dyspepsia symptom score on days 3 and 7 of treatment, but significantly greater symptom improvement was seen in the PPI group than the H₂RA + Prok group on days 14 and 28 of treatment. The proportion of subjects reporting that they were satisfied or very satisfied was significantly higher in the PPI group than in the H₂RA + Prok group on day 28. PPI therapy was the only significant predictor of treatment response, defined as a total symptom score improvement of ≥ 50%.

In a recent meta-analysis of PPI treatment for FD, the dysmotility-like subgroup did not respond to PPI therapy, unlike the reflux and ulcer-like subgroup[25]. The severity of heartburn at baseline in FD patients influences treatment response to PPI or H₂RA therapy[10]. We assessed heartburn symptoms at baseline in a separate study, finding no difference between groups in the pretreatment heartburn symptom score (data not shown). Our results suggest that powerful suppression of acid secretion by PPIs is also important in the treatment of dysmotility-like symptoms in Japanese patients with FD. We saw similar symptom score improvements in both groups until day 7 of treatment. This may represent a placebo response, because it is well known that the placebo response can be substantial in trials of GI disorders, including FD[10]. There have been reports of a placebo effect until day 7 of treatment with a PPI[26], and of the need for a 7-d run-in period to minimize the placebo effect in FD clinical trials[27-29], so a similar placebo response lasting until day 7 of treatment was also possible in this study. The absence of any further improvement in dysmotility-like dyspepsia symptoms between day 7 and days 14 or 28 in the H₂RA + Prok group, and the lack of significant change in subject satisfaction rates from day 14 to 28, indicates the development of H₂RA tolerance[30].

Stratifying the study sample by H. pylori status showed that significantly better symptom improvement was seen in the PPI group than the H₂RA + Prok group in both H. pylori-positive and -negative subjects. No influence of H. pylori status was seen in either treatment group in our study. In the studies by Talley et al[5], no significant difference was seen in the rate of complete symptom resolution after 28 d of treatment between H. pylori-positive and -negative subjects in the ulcer-like, reflux-like, or dysmotility-like symptom subgroups in either treatment arm, although these were only exploratory analyses. Although H. pylori status did not significantly influence the response to omeprazole, this does not exclude the possibility of a small true difference between H. pylori-positive and -negative patients in the effect of acid inhibition on FD. Intragastric pH is higher in patients taking a PPI who are infected with H. pylori[31]. PPI therapy may therefore be more effective in H. pylori-positive patients with NUD, as one study has suggested[28]. Pooling all trial data suggests that symptom responses are similar in H. pylori-positive and -negative patients with NUD. H. pylori status is unlikely to have a clinically important impact on the efficacy of treatments in this patient group.

In this study, symptoms improved over time regardless of H. pylori status in the PPI group, whereas no further symptom improvement was seen in the H₂RA + Prok group after day 7 of treatment in both H. pylori-positive and -negative subjects, indicating tolerance to treatment. Loss of the suppressive effect on acid secretion by H₂RAs has been reported in H. pylori-negative patients as the duration of treatment increases[32], whereas in this study tolerance was seen from day 7 of treatment in the H₂RA + Prok group.

Limitations of this study include the small number of subjects and the fact that it was not a placebo-controlled trial. Consideration of the Japanese medical system tells us that clinical trials of treatments for FD, a condition not covered by medical insurance, conducted with the participation of general medical clinics will be limited in scope. Nevertheless, this is the first published report of a randomized comparative trial of PPI monotherapy and H₂RA + Prok combination therapy in the treatment of FD in Japanese subjects.

We demonstrated that, even in Japan with its high proportion of H. pylori-positive patients, PPI monotherapy significantly improves not only ulcer and reflux-like symptoms, but also dysmotility-like symptoms, better than H₂RA + Prok combination therapy. In particular, tolerance to H₂RA + Prok combination therapy was seen regardless of H. pylori status. The prevalence of H. pylori infection is expected to decline in Japan in the future[33], leading to increased gastric acid secretion, so suppression of acid secretion will likely become even more important. The American College of Gastroenterology guidelines for the management of dyspepsia recommend a PPI as the treatment of first choice in regions with a low prevalence of H. pylori infection, with investigations and other therapies for those who fail to respond[29]. In Japan, where the prevalence of H. pylori infection remains high, upper GI endoscopy is considered mandatory for the exclusion of malignancy. Powerful suppression of acid secretion, such as a PPI provides, is the most effective therapy for treatment of all dyspeptic symptoms in Japanese patients, both ulcer- and reflux-like and dysmotility-like symptoms. Of particular interest is our finding that PPI therapy is useful in the treatment of dysmotility-like symptoms, usually considered less responsive to PPIs. In other words, dysmotility-like symptoms of FD are also an acid-related disorder, for which suppression of acid secretion is the most effective therapy. PPIs are extremely effective in the treatment of all symptoms of FD, and should be the treatment of first choice in Japanese patients with FD.