J Gastroenterol 2006; 41:513523 DOI 10.

1007/s00535-006-1847-5

Review Therapeutic strategies for functional dyspepsia and the introduction of the Rome III classication
Hidekazu Suzuki, Toshihiro Nishizawa, and Toshifumi Hibi
Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Although placebo response rates in clinical trials for functional dyspepsia (FD) are more than 30%, a recent meta-analysis based on randomized controlled trials (RCTs) showed that antisecretory drugs were more or less superior to placebos. On the other hand, large-scale RCTs on the efcacy of treatment with prokinetics on FD are still needed. Indications for antibiotic eradication therapy for Helicobacter pylori-positive FD are still controversial, but there seems to be a small but signicant therapeutic gain achieved with H. pylori eradication. Since preprandial and postprandial symptomatic disturbances are very important targets for FD treatment, ghrelin, a novel appetite-promoting gastrointestinal peptide that also promotes gastric motility or basal acid secretion can be expected to be a therapeutic target. In the recently published Rome III classication, FD is redened for patients with symptoms thought to originate from the gastroduodenal region, specically epigastric pain or burning, postprandial fullness, or early satiation, and it is divided into the subcategories postprandial distress syndrome and epigastric pain syndrome. These new criteria are of value in clinical practice, for epidemiological, pathophysiological, and clinical research, and for the development of new therapeutic strategies. Key words: postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), prokinetics, ghrelin, placebo

Conceptual history and updated denition of functional dyspepsia Most patients do not recognize dyspepsia, and historically physicians have interpreted dyspepsia in various ways. Dyspepsia has often been loosely dened; the most widely applied denition is the formulation of the Rome Working Teams, namely, chronic or recurrent pain or discomfort centered in the upper abdomen,1 now updated as the Rome III classication.2 Predominant epigastric pain or discomfort helps to distinguish dyspepsia from gastroesophageal reux disease (GERD); in the latter, the dominant complaint is typically heartburn or acid regurgitation, but there may be a distinct epigastric component, which causes confusion.3 According to recent practice guidelines for the management of dyspepsia developed by the Practice Parameters Committee of the American College of Gastroenterology,4 dyspepsia is dened as chronic or recurrent pain or discomfort centered in the upper abdomen. Discomfort is dened as a subjective negative feeling that is nonpainful, and is considered to incorporate a variety of symptoms, including early satiety, bloating, upper abdominal fullness, or nausea.1,4 However, it has remained unsettled whether discomfort is a mild variant of pain or a separate symptom complex. In the new Rome III classication, which is based on the consensus opinion of an international panel of clinical investigators who reviewed the available evidence,2 functional dyspepsia (FD) is dened as the presence of symptoms thought to originate in the gastroduodenal region, in the absence of any organic, systemic, or metabolic disease that is likely to explain the symptoms.5 In the Rome III classication of functional gastrointestinal (GI) disorders,2 FD is a subcategory of the functional gastroduodenal disorders.5 In this classication system, there are four categories of functional gastroduodenal disorders:5 category B1, FD, comprising postprandial

Received: May 1, 2006 / Accepted: May 9, 2006 Reprint requests to: H. Suzuki

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distress syndrome (PDS; B1a) and epigastric pain syndrome (EPS; B1b); category B2, belching disorders, comprising aerophagia (B2a) and unspecied excessive belching (B2b); category B3, functional nausea and vomiting disorders, comprising chronic idiopathic nausea (B3a), functional vomiting (B3b), and cyclic vomiting syndrome (B3c); and category B4, rumination syndrome. Although the Rome II classication6 dened FD as at least 12 weeks, not necessarily consecutive, within the preceding 12 months of persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen), the new Rome III classication denes FD on the basis of symptoms originating 6 months before diagnosis and currently active for 3 months.2 Thus, the Rome III classication has a less restrictive time frame than Rome II (12 weeks of symptoms over 12 months) and is easier to understand and apply in research and clinical practice. Previously, the Rome II classication divided patients having a wide range of symptoms of dyspepsia into four groups on the basis of the major symptomatic pattern, namely, reux-like, ulcer-like, dysmotility-like, or nonspecic FD,7 and excluded patients with predominant heartburn (reux-like pattern) from the dyspepsia spectrum. Recent studies, however, have reported that the predominant symptom approach does not reliably identify all patients with GERD.811 In general, the overlap of GERD with PDS or EPS is probably frequent and needs to be carefully considered in both clinical practice and experimental trials. The Rome III committee recommends that the presence of frequent and typical reux symptoms should lead to a provisional diagnosis of GERD.12 On the other hand, the presence of heartburn per se does not exclude a diagnosis of PDS or EPS if dyspepsia persists despite a trial of adequate acid suppression therapy. Overlap between dyspeptic symptoms and irritable bowel syndrome (IBS) is also commonly observed, and overlap between IBS on the one hand and PDS or EPS on the other hand is likely to occur. Now the Rome III committee has nally proposed to dene FD at two levels.5 A general, more umbrella denition of FD, to be used mainly for clinical purposes, is provided under category B1, although further research to provide a more specic denition is ongoing. However, particularly for pathophysiological and therapeutic research purposes, it is recommended that the newly dened subcategories, PDS (meal-induced dyspeptic symptoms; B1a) and EPS (B1b), should be used operatively.5 The two subcategories PDS and EPS are likely to be very useful in clinical practice as well as in investigative settings.

Management of functional dyspepsia Once a diagnosis of FD is conrmed by a negative endoscopy, an empirical trial of therapy is commonly prescribed. However, the benets of all therapies for this condition have been questioned. On the other hand, many patients do not require medication for dyspepsia, only reassurance and education. It is therefore important for the clinician to explain the meaning of the symptoms and their benign nature. Ascertaining why a patient with long-standing symptoms has presented on this occasion for care can be helpful for identifying those patients who fear that there is an underlying serious disease or those with specic sources of psychological distress that can be addressed. Potential precipitating factors in dyspepsia remain poorly dened. High-fat meals should be avoided, and eating frequent, small meals throughout the day can sometimes be helpful. Specic foods that precipitate symptoms can be avoided. Food intolerance is uncommon, however, and food allergy is very rare. The placebo response in FD is approximately 30%40% among patients in randomized controlled trials (RCTs).11 The placebo response may in part reect the natural uctuations of upper GI tract symptoms, although this is not the only likely explanation.13 According to a recent report by Talley et al.,14 independent predictors of a low placebo response are low body mass index (BMI) and a more consistent predominant symptom pattern (both P < 0.05), but there is no association with age, sex, center type, baseline symptom score, baseline or change in gastric emptying, or baseline quality of life (QOL). Their data indicate that, aside from BMI and predominant symptom pattern, symptom severity, age, sex, center type, and gastric emptying are not useful predictors of the placebo response.

Meta-analyses of the effects of antisecretory drugs and prokinetics (Table 1) In view of therapeutic advances, Finney et al.15 carried out a meta-analysis of results from 18 randomized, controlled clinical studies to provide an overview of clinical trials involving treatment of FD and showed that antisecretory treatment with an H2-receptor antagonist (H2RA; cimetidine or ranitidine) offered little advantage over placebo, whereas treatment with the prokinetics cisapride or domperidone produced signicantly better results than placebo for treatment of FD. Allescher et al.16 performed a meta-analysis of 19 studies of prokinetics (cisapride, domperidone) and ten studies of H2RA (cimetidine, ranitidine), evaluating a total of 1540 patients for H2RA (H2RA, n = 786; placebo, n = 754) and 1235 patients for prokinetics

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Table 1. Meta-analyses on the relative effect of antisecretory drugs or prokinetics versus a placebo in the treatment of functional dyspepsia Abraham et al.18 Finney et al.15 Number of patients RR reduction by H2RA Number of patients RR reduction by PPIs Number of patients RR reduction by prokinetics 596 0.36 1235 0.62 1053 0.53 339 0.00 628 0.24 Redstone et al.17 940 0.18 Allescher et al.16 1540 0.34 All trials 2185 0.32 High-quality trials 838 0.13 Moayyedi et al.19 2164 0.22 3293 0.14 1053 0.48

H2RA, H2-receptor antagonist; RR, relative risk; PPIs, proton-pump inhibitors

(prokinetics, n = 616; placebo, n = 619). They reported that the probability for treatment success compared with placebo was 0.2026 for H2RA and 0.4029 for prokinetics and concluded that both treatments are signicantly more effective than placebo in the symptomatic treatment of nonulcer dyspepsia, with prokinetics being more effective than a histamine H2RA.16 A meta-analysis of randomized controlled clinical trials by Redstone et al.17 also found some evidence that H2RA is superior to placebo in FD (odds ratio in favor of active drug, 1.48 for global assessment of dyspepsia symptoms, 2.3 for improvement of epigastric pain, and 1.8 for complete relief of epigastric pain), but larger studies evaluating higher doses of H2RA and of longer duration are still needed to determine the exact size of the effect. Abraham et al.18 conducted a systematic review of RCTs for endoscopically investigated dyspepsia (1979 2003) using the Jadad score, which differentiates studies as high quality (13/5) or poor quality (45/5). They concluded that the magnitude of benet derived from therapies with prokinetics or H2RA reported in previous meta-analyses had been overestimated and that the quality of the trials affects the estimation of treatment efcacy.18 Moayyedi et al.19 performed a meta-analysis to evaluate the effectiveness of several drugs in improving either individual or global dyspepsia symptom scores and also QOL scores of patients with nonulcer dyspepsia (NUD) and showed that prokinetics (14 trials with dichotomous outcomes, 1053 patients in all), H2RAs (11 trials, 2164 patients), and proton-pump inhibitors (PPIs; eight trials, 3293 patients) were signicantly more effective than placebo. However, they found that trials evaluating prokinetics therapy were difcult to interpret, and the meta-analysis result might reect publication bias.19

Trials evaluating the effect of antisecretory drugs or prokinetics (Table 2) In 2002, Wong et al.20 found in a randomized placebocontrolled study of Chinese patients (n = 453) that treatment with lansoprazole (30 or 15 mg daily) is not superior to placebo for the management of FD. On the other hand, Bollong-Sternevald et al.21 evaluated the effect of another PPI, omeprazole, in a study of 197 FD patients, randomly allocated to a double-blind treatment with omeprazole 20 mg or placebo for 14 days, and concluded that a subset of patients with FD responds to therapy with omeprazole. They also analyzed pooled data of patients from two placebo-controlled trials (n = 826) with a diagnosis of FD who were treated with omeprazole, 10 or 20 mg once daily, for 4 weeks and reported that an early response to treatment with a PPI (during the rst week), seems to predict the outcome after 4 weeks.22 Peura et al.8 also compared the efcacy of lansoprazole with placebo in relieving upper abdominal discomfort in 921 patients with FD. In their study, patients were randomly assigned to receive lansoprazole 15 mg, lansoprazole 30 mg, or placebo daily for 8 weeks. According to their results, lansoprazole, at a daily dose of 15 or 30 mg, is signicantly better than placebo in reducing symptoms of persistent or recurrent upper abdominal discomfort accompanied by at least some symptoms of heartburn.8 On the other hand, Jones and Baxter23 conducted a double-blind, parallel-group, randomized, multicenter study of 32 general practices in the United Kingdom, with 213 patients randomized to receive lansoprazole 30 mg daily and 219 to receive ranitidine 150 mg twice daily for 4 weeks and concluded that patients presenting with ulcer-like or reux-like symptoms in general practice obtained superior symptom relief from lansoprazole 30 mg daily than from ranitidine 150 mg twice daily.

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Table 2. Randomized controlled trials on the effect of antisecretory drugs or prokinetics in the treatment of functional dyspepsia (nonulcer dyspepsia) Reference Wong et al.20 Number of patients 453 Drug Lansoprazole Dose Placebo 15 mg/day 30 mg/day Placebo 40 mg/day Placebo 10 mg/day 20 mg/day 22.5 mg/day 30 mg/day 300 mg/day Placebo 15 mg/day 30 mg/day Treatment period 4 weeks Effective rates 30% (45/152) 23% (35/152) 44% (35/149) 18% (17/96) 29% (29/100) 60% (84/141) 59% (83/140) 59% (84/143) 61% (87/142) 55% (117/213) 33% (73/219) 29% (80/273) 44% (114/258) 44% (118/271) Efcacy Not effective

Bolling-Sternevald et al.21 Hallerback et al.50

197 566

Omeprazole Mosapride

2 weeks 6 weeks

Effective Not effective

Jones and Baxter23 Peura et al.8

432 921

Lansoprazole Ranitidine Lansoprazole

4 weeks 8 weeks

Effective Effective

Recently, Seno et al.24 examined 64 FD patients without Helicobacter pylori infection who were randomly assigned mosapride (15 mg/day), famotidine (40 mg/ day), or tandospirone (30 mg/day) during an 8-week treatment period and found signicant improvements of FD symptoms in mosapride- and famotidine-treated patients (P < 0.01), and famotidine was signicantly more effective than mosapride (P < 0.05). Kato et al.25 performed a multicenter, randomized, double-blind, placebo-controlled crossover trial for patients with FD dened by the Rome II criteria and demonstrated a signicant improvement in Gastrointestinal Symptoms Rating Scale (GSRS) scores for abdominal pain (P = 0.007), indigestion, and reux syndrome after famotidine treatment. Holtmann et al.26 performed a double-blind, placebo-controlled crossover trial starting in random order with either an active drug (ranitidine, 150 mg twice daily) or placebo for the treatment of FD and reported that patients with reux-like symptoms and greater psychological disturbance are more likely to respond to an acid-lowering compound. However, because these two studies were crossover trials, the effect of the previous drug cannot be strictly ruled out when assessing each test drug. PPIs also produce a relative risk reduction of approximately 30%, and the quality of the trials is better.27 Talley et al.28 reported that omeprazole at standard (20 mg) and low (10 mg) doses is modestly superior to placebo for FD, but not in patients with dysmotility-like dyspepsia. An economic model suggests that PPI therapy is cost-effective for FD in the United States.11 However, in a recent randomized trial of 453 patients from Hong Kong, the proportion of patients achieving complete relief from dyspepsia with lansoprazole 30 or

60 mg was 23% and 23%, respectively, compared with 30% for placebo.20 In contrast, another recent trial reported a signicant benet from lansoprazole in a U.S. population.8 Helicobacter pylori status is unlikely to affect the therapeutic outcome of acid suppression therapy in FD.11 Large trials have failed to identify any difference in therapeutic outcome in H. pylori-positive versus H. pylori-negative patients, although Blum et al.29 did identify a superior response to PPI therapy in H. pyloripositive patients.

Helicobacter pylori eradication (Tables 3 and 4) Eradication of H. pylori in FD is still controversial. The 2003 revision of the guidelines for the diagnosis and treatment of H. pylori infection for physicians in routine medical practice by the Japanese Society for Helicobacter Research30 states that some clinical and economic benet has been shown [against FD], but global consensus has not necessarily been reached. Conclusions drawn from previous studies are not unanimous, and further reports are awaited regarding the signicance of the eradication therapy. FD is listed as a third-category indication for H. pylori eradication.30 In 1998, McColl et al.31 performed a randomized, placebo-controlled trial comparing the efcacy of treatment for 2 weeks with 20 mg of omeprazole orally twice daily, 500 mg of amoxicillin three times daily (with 500 mg of tetracycline three times daily substituted for amoxicillin in patients allergic to penicillin), and 400 mg of metronidazole three times daily (160 patients) with

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Table 3. Randomized controlled trials on the effect of Helicobacter pylori eradication therapy in the treatment of functional dyspepsia (nonulcer dyspepsia) McColl et al.31 Number of patients (eradicated/noneradicated) Place Single/multicenter Eradication protocol Control Eradication period Observation period Effective rates (%) (eradicated/noneradicated) Efcacy 154/154 UK Single center OAM Omeprazole 40 mg/day 14 days 1 year 21/7 Effective Blum et al.32 164/164 Europe, Canada, South Africa Multicenter OAC Omeprazole 40 mg/day 7 days 1 year 27.4/20.7 Talley et al.35 150/143 USA Multicenter OAC Placebos 14 days 1 year 46/50 Moayyedi et al.36 880/871 UK Field study OCT Placebos 7 days 2 years 72/67 Effective Dhali et al.37 32/30 India Single center BTM Sucralfate 4 g/day 14 days 3 months 81/33 Effective

OAM, omeprazole, amoxicillin, metronidazole; OAC, omeprazole, amoxicillin, clarithromycin; OCT, omeprazole, clarithromycin, tetracycline; BTM, bismuth, tetracycline, metronidazole

Table 4. Meta-analyses of the effect of H. pylori eradication therapy on the treatment of functional dyspepsia (nonulcer dyspepsia) Jaakkimainen et al.38 Number of RCTs Number of patients Relative risk reduction Odds ratio Efcacy
RCTs, randomized controlled trials

Moayyedi et al.39 9 2541 0.09 Effective

Laine et al.34 7 1544 1.29

Moayyedi et al.40 17 3566 0.10 Effective

5 1.9 Effective

that of omeprazole alone (158 patients) for resolving symptoms of dyspepsia in patients with H. pylori infection but no evidence of ulcer disease on upper GI endoscopy. One year later, they found that dyspepsia had resolved in 33 of 154 patients (21%) in the group given omeprazole and antibiotics, as compared with 11 of 154 (7%) in the group given omeprazole alone [95% condence interval (CI), 7%22%; P < 0.001]. Moreover, among the patients in the group given omeprazole and antibiotics, the symptoms resolved in 26 of the 98 patients (27%) who had had symptoms for 5 years or less, but in only 7 of the 56 patients (12%) who had had symptoms for more than 5 years (P = 0.03). Their results clearly suggest that in patients with H. pylori infection and FD, H. pylori eradication treatment is more likely to resolve symptoms than treatment with omeprazole alone.31 On the other hand, in the same issue of the New England Journal of Medicine, Blum et al.32 reported the results of a double-blind, multicenter trial of patients with both H. pylori infection and dyspeptic symptoms, which showed that treatment was successful in 27.4% of patients in the eradication group and in 20.7% of those in the group treated with omeprazole alone (P = 0.17). They concluded that in patients with FD, the eradica-

tion of H. pylori is not likely to relieve symptoms.32 Moreover, two high-quality meta-analyses have reached opposite conclusions, which likely can be explained by which trials were included or excluded in each systematic review.33,34 Talley et al.35 randomly assigned 170 H. pylori-infected patients with NUD to receive 20 mg of omeprazole, 1000 mg of amoxicillin, and 500 mg of clarithromycin twice daily for 14 days (OAC group), and 167 such patients to receive placebos identical in appearance; all patients were then followed through regular visits for 12 months. At 12 months, there was no signicant difference between groups in the rate of successful treatment (OAC group, 46%; placebo group, 50%; relative likelihood of success with OAC treatment, 0.93; 95% CI, 0.731.18; P = 0.56), and they concluded that there was no evidence that curing H. pylori infection in patients with NUD leads to the relief of symptoms. Moayyedi et al.36 investigated whether H. pylori eradication could lower the prevalence of dyspepsia in a community or improve the QOL in a double-blind RCT and reported that community screening and treatment for H. pylori produced only a 5% reduction in dyspepsia with no impact on QOL (Table 3).

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In India, Dhali et al.37 performed a randomized study to evaluate the efcacy of anti-H. pylori treatment versus sucralfate in 62 patients with H. pylori-positive NUD. Their results showed that triple therapy eradicated H. pylori in 88% of patients with NUD and H. pylori infection and was superior to sucralfate in producing symptom relief (81% vs. 33%, P = 0.0003) (Table 3).37 In a meta-analysis, Jaakkimainen et al.38 examined the association between H. pylori infection and NUD and assessed the effect of eradicating H. pylori on dyspeptic symptoms in patients with NUD. In the eradication trials, the summary odds ratio for alleviation of dyspeptic symptoms in patients with NUD in whom H. pylori was eradicated was 1.9 (1.32.6), and dyspeptic symptoms of patients with NUD in whom H. pylori was eradicated were alleviated. Moayyedi et al.39 evaluated the efcacy and cost effectiveness of H. pylori eradication in patients with H. pylori-positive NUD in a systematic review of RCTs comparing H. pylori eradication with placebo or another drug treatment and showed that H. pylori eradication treatment was signicantly superior to placebo in treating NUD (relative risk reduction 9%; 95% CI, 4%14%); one case of dyspepsia was cured for every 15 people treated. Finally, they noted that although H pylori eradication may be a cost-effective treatment for NUD in infected patients, further evidence is needed regarding the willingness of the decision maker to pay for relief of dyspepsia.39 On the other hand, in a 2001 meta-analysis of RCTs, Laine et al.34 assessed the effect of eradication therapy for H. pylori on symptoms of NUD. According to their analysis, the odds ratio for success in treatment NUD with H. pylori eradication therapy compared with control therapy was 1.29 (95% CI, 0.891.89; P = 0.18) (Table 4), providing little support for the use of H. pylori eradication therapy in patients with NUD.34 Moayyedi et al.,40 in an updated systematic review of 21 RCTs to determine the effect of H. pylori eradication on dyspepsia symptoms in patients with NUD, reported a 10% relative risk reduction in the H. pylori eradication group compared with placebo (the number of people that needed to be treated to cure one case of dyspepsia was 14; Table 4), suggesting that H. pylori eradication therapy has a small but statistically signicant effect on H. pylori-positive NUD. Follow-up data for longer than 1 year are generally lacking, but one 5-year study suggests that any benet achieved will persist.41 The evidence indicates that it is acceptable to offer H. pylori eradication therapy to infected patients with FD. The results also imply that offering H. pylori eradication therapy empirically to infected patients with otherwise uninvestigated dyspepsia is reasonable even if ulcer disease is unlikely. Moreover, H. pylori eradication in patients with documented

FD may help prevent ulcer disease, although convincing evidence is not available. In a RCT of 161 patients with functional dyspepsia, Hsu et al.42 reported that on repeat endoscopy at the 1-year follow-up, two patients in the H. pylori eradication treatment group (3%) and six in the placebo group (8%) developed peptic ulcers.42 We recently reported that successful H. pylori eradication improved the QOL of patients with FD, in particular H. pylori-positive patients with ulcer-like or dysmotility-like FD.43 In that study,43 we used GSRS scoring for subgroup categorization43,44 of patients visiting the Helicobacter outpatient clinic of Keio University Hospital. On the basis of their scores in the ve symptom categories of the GSRS,45 patients in whom the reux score was the highest were excluded as having symptomatic GERD; patients in whom the abdominal pain score was the highest were categorized as having ulcer-like FD, which is approximately equivalent to EPS in Rome III (B1b); patients in whom the indigestion score was the highest, assessed based on meal-related questions, were categorized as having dysmotility-like FD, which is approximately equivalent to PDS in Rome III (B1a); and patients with a constipation or diarrhea score of more than 3 were excluded as having IBS (Fig. 1). The remaining patients were categorized as having nonspecic-type (unspecied) disorders (Fig. 1). Although this simple and rough categorization using the GSRS score emphasized the major symptoms, it might be a practical approach for diagnosing PDS, which mostly overlaps with dysmotility-like FD of the Rome III classication, and EPS, which mostly overlaps with ulcer-like FD.

Prokinetics A Cochrane review of 12 trials with prokinetics comprising 829 patients showed that there was a relative risk reduction of 50%, compared with placebo, but most of the studies were with cisapride.27 Moreover, analysis of the studies suggested that publication bias at least partly explains the apparent benets of prokinetic therapy. Prokinetics should be reserved for difcult cases, because options in the United States are few and current agents (e.g., metoclopramide, erythromycin, tegaserod) have limited or poorly established efcacy, or side effects are common.46 Routine use of gastric-emptying treatments is not recommended because improvements in gastric emptying do not correlate well with symptom improvement.47,48 Drugs that relax the gastric fundus [e.g., tegaserod, cisapride, sumatriptan, buspirone, clonidine, some selective serotonin reuptake inhibitors (SSRIs), and nitric oxide (NO) donors] may theoretically improve some symptoms of dysmotility-like dyspepsia (e.g., early satiety), but adequate RCTs are lacking.49

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Symptoms thought to originate in the gastroduodenal region

519

Dyspepsia uninvestigated
Structural disease
Reflux score is the highest

One or more of: a. Bothersome postprandial fullness b. Early satiation c. Epigastric pain Criteria fulfilled for the last 3 months d. Epigastric burning with symptom onset

Investigated Functional GSRS

Abdominal pain score is the highest

at least 6 months before diagnosis

Constipation or diarrhea score is more than 3

ENRD or Functional heartburn

Indigestion score is the highest

Remaining patients

Functional bowel disorders (C)(IBS etc.)

Unspecified (non-specific-type FD)

Postprandial Distress Syndrome; PDS (B1a) (dysmotility-like FD)

Epigastric Pain Syndrome; EPS (B1b) (ulcer-like FD)

Functional dyspepsia (B1)

Fig. 1. Proposed subcategorization of functional dyspepsia (FD) according to the Gastrointestinal Symptom Rating Scale (GSRS). PDS, postprandial distress syndrome; EPS, epigastric pain syndrome; ENRD, endoscopy-negative reux disease; IBS, irritable bowel syndrome

In 2002, Hallerback et al.50 compared the efcacy of mosapride, a 5-hydroxytryptamine 4 (HT4)-receptor agonist, compared with placebo in the treatment of FD (Table 2) in a double-blind, prospective, multicenter, multinational study and found that treatment of FD with mosapride was not superior to placebo. On the other hand, Otaka et al.51 evaluated the efcacy of an H2RA (famotidine) and mosapride by randomizing FD patients to receive famotidine (20 mg/day) or mosapride (15 mg/day) for 4 weeks and demonstrated that both famotidine and mosapride had benecial effects regardless of FD subtype or age and sex of the patient, with no signicant difference in the efcacy of these two drugs in relieving FD symptoms.51 On the other hand, Kinoshita et al.52 compared the therapeutic effects of famotidine, mosapride, and tandospirone for controlling the symptoms of fully examined FD patients randomly assigned to receive one of the three drugs. They found that all of the drugs had benecial effects; famotidine was the most effective for symptom relief, signicantly more effective than tandospirone, while the effect of mosapride was similar to that of famotidine.52 Recently, the results from a large-scale comparative study on the treatment of FD, especially ulcer-like and dysmotility-like FD (Japan Mosapride Mega-Study, JMMS) were reported at the 92nd general meeting of the Japanese Society of Gastroenterology (April 2022, 2006). (Also reported at the 107th annual meeting of the American Gastroenterological Association Institute, May 23, 2006.53) These results showed that symptoms such as feeling of stasis or epigastric pain

were alleviated by both mosapride and teprenone (a gastroprotective agent), with mosapride having a modestly superior effect, suggesting that further practical applications can be expected. Because the stomach functions as a reservoir to accommodate the intake of food and liquid, disturbances of this function, such as adaptive relaxation, may cause epigastric fullness or early satiety.5456 Restoration of gastric accommodation with a fundus-relaxing drug, sumatriptan (a 5-HT1 agonist), is reported to alleviate early satiety.56 On the other hand, Hayakawa et al.57 examined the effects of a traditional Chinese herbal medicine (kampo), rikkunshi-to (liu-jun-zi-tang), on gastric adaptive relaxation in isolated guinea pig stomachs. They reported that rikkunshi-to induced gastric adaptive relaxation at a low intragastric pressures, increasing both the volume percent of the gastric adaptive relaxation and the absolute intragastric volume, whereas metoclopramide (2 mg/ml), trimebutine (6 mg/ ml), and cisapride (2 mg/ml) did not affect gastric adaptive relaxation, suggesting that rikkunshi-to both promoted gastric adaptive relaxation and relieved FD symptoms.57 Kido et al.58 also recently evaluated the effects of rikkunshi-to on the delay of gastric emptying induced by a NO synthase inhibitor, NG-nitro-l-arginine and concluded that rikkunshi-to ameliorated abnormalities of NO-mediated gastric functions such as delayed gastric emptying. They identied hesperidin and l-arginine as two of the active ingredients contributing to the ability of rikkunshi-to to facilitate gastric emptying.58

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Tegaserod, a 5-HT4-receptor agonist, also enhances gastric emptying. Tack et al.59 examined the effect of tegaserod on gastric compliance, accommodation, and perception of distension in humans in a double-blind, randomized, three-way crossover design. According to their study, tegaserod allowed for larger intraballoon volumes both before and after a meal, warranting the investigation of the therapeutic potential of tegaserod in dyspeptic patients with impaired accommodation.59 Recently, Riezzo et al.60 reported on 25 cancer patients treated with standard dosages of antiemetics and chemotherapies and concluded that chemotherapy might induce upper GI symptoms suggestive of motility disorders.

depression that are easily available in primary care. In their review,65 11 of 13 articles showed benecial results of psychopharmacologic drugs, although this tendency was not conrmed by statistical analysis, owing to the poor quality of the trial reports. Among them, three used a combination therapy of medications for treating physical and psychiatric conditions,6668 and in two of these three trials, the combination therapy produced favorable results. This systematic review showed that agents for treating anxiety, neurosis, or, especially, depression may have a benecial effect in the treatment of FD patients. Although there are no studies comparing the efcacy of antianxiety or antidepressive agents with that of antisecretory or prokinetic agents, their efcacy can be expected to be the same as that of antisecretory or prokinetic agents.

Antidepressants Antidepressants are also of uncertain efcacy in FD but are often prescribed.47,61 Tanum and Malt61 performed a double-blind placebo-controlled study with mianserin to investigate the efcacy of this antidepressant in functional GI disorders and showed that patients taking mianserin reported less abdominal pain, symptoms of abdominal distress, and functional disability than those given a placebo (P < 0.001). However, one problem with the study by Tanum and Malt61 is that patients with IBS were included. On the other hand, Mertz et al.62 evaluated the effect of amitriptyline (50 mg/day) for 4 weeks on FD in a RCT and reported a benecial effect of lowdose amitriptyline seen in FD; although no relationship with changes in perception of gastric distension or measures of arousal from sleep was observed, tolerance to aversive visceral sensations was possibly increased (Table 5). However, as the number of patients in this study was only seven, these results should be conrmed by a larger study in the future. Data on SSRIs are limited. Psychological therapies are promising, particularly hypnotherapy, but more data are needed in larger patient populations before these can be recommended for routine use.63,64 Hojo et al.65 recently conducted a systematic review of trials with agents efcacious for anxiety, neurosis, or Expected therapeutic targets in the eld of FD To treat the symptoms of FD, including preprandial epigastric pain or postprandial gastric discomfort, the regulation of feelings for hunger or satiety may be an important target of novel strategies for the control of FD. Ghrelin, which is a novel appetite-promoting peptide69 secreted mainly from the gastric fundus, is reported to stimulate gastric acid secretion and gastrointestinal motility70,71 by the premature induction of gastric phase III of the migrating motor complex72 and is a candidate novel target of FD treatment. We previously showed reduced gastric ghrelin content in H. pylori-associated gastritis73,74 and enhanced ghrelin secretion under emotional stress,75 suggesting that the stomach might be responsive not only to an intraluminal antigen but also to emotional stimuli. In clinical settings, plasma ghrelin concentrations correlate well with serum concentrations of pepsinogen (PG) I and the PG I/II ratio, and inversely correlate with the progression of gastric mucosal atrophy.76,77 On the other hand, plasma ghrelin levels are increased when peptic ulceration is present.78,79 With regard to the role of ghrelin in FD, Shinomiya et al.80 reported a signicant correlation between circulat-

Table 5. Randomized controlled trials on the effect of antidepressants in the treatment of FD or FGID Tanum and Malt61 Number of patients Disease Drug Treatment period (weeks) Observation period (weeks) Effective rate (%) 49 FGID Mianserin 120 mg/day 7 7 73 Mertz et al.62 7 FD Amitriptyline 50 mg/day 4 8 71

FD, functional dyspepsia; FGID, functional gastrointestinal disorder

H. Suzuki et al.: Treatment of functional dyspepsia

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12. Thomson AB, Barkun AN, Armstrong D, Chiba N, White RJ, Daniels S, et al. The prevalence of clinically signicant endoscopic ndings in primary care patients with uninvestigated dyspepsia: the Canadian Adult Dyspepsia Empiric TreatmentPrompt Endoscopy (CADET-PE) study. Aliment Pharmacol Ther 2003;17: 148191. 13. Thompson WG. Placebos: a review of the placebo response. Am J Gastroenterol 2000;95:163743. 14. Talley NJ, Locke GR, Lahr BD, Zinsmeister AR, CohardRadice M, DElia TV, et al. Predictors of the placebo response in functional dyspepsia. Aliment Pharmacol Ther 2006;23:923 36. 15. Finney JS, Kinnersley N, Hughes M, OBryan-Tear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroenterol 1998;26:31220. 16. Allescher HD, Bockenhoff A, Knapp G, Wienbeck M, Hartung J. Treatment of non-ulcer dyspepsia: a meta-analysis of placebocontrolled prospective studies. Scand J Gastroenterol 2001;36: 93441. 17. Redstone HA, Barrowman N, Veldhuyzen Van Zanten SJ. H2receptor antagonists in the treatment of functional (non-ulcer) dyspepsia: a meta-analysis of randomized controlled clinical trials. Aliment Pharmacol Ther 2001;15:12919. 18. Abraham NS, Moayyedi P, Daniels B, Veldhuyzen Van Zanten SJ. Systematic review: the methodological quality of trials affects estimates of treatment efcacy in functional (non-ulcer) dyspepsia. Aliment Pharmacol Ther 2004;19:63141. 19. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2004;(4):CD001960. 20. Wong WM, Wong BC, Hung WK, Yee YK, Yip AW, Szeto ML, et al. Double blind, randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients. Gut 2002;51:5026. 21. Bolling-Sternevald E, Lauritsen K, Aalykke C, Havelund T, Knudsen T, Unge P, et al. Effect of profound acid suppression in functional dyspepsia: a double-blind, randomized, placebocontrolled trial. Scand J Gastroenterol 2002;37:1395402. 22. Bolling-Sternevald E, Lauritsen K, Talley NJ, Junghard O, Glise H. Is it possible to predict treatment response to a proton pump inhibitor in functional dyspepsia? Aliment Pharmacol Ther 2003;18:11724. 23. Jones RH, Baxter G. Lansoprazole 30 mg daily versus ranitidine 150 mg b.d. in the treatment of acid-related dyspepsia in general practice. Aliment Pharmacol Ther 1997;11:5416. 24. Seno H, Nakase H, Chiba T. Usefulness of famotidine in functional dyspepsia patient treatment: comparison among prokinetic, acid suppression and antianxiety therapies. Aliment Pharmacol Ther 2005;21(Suppl 2):326. 25. Kato M, Watanabe M, Konishi S, Kudo M, Konno J, Meguro T. Randomized, double-blind, placebo-controlled crossover trial of famotidine in patients with functional dyspepsia. Aliment Pharmacol Ther 2005;21(Suppl 2):2731. 26. Holtmann G, Kutscher SU, Haag S, Langkafel M, Heuft G, Neufang-Hueber J, et al. Clinical presentation and personality factors are predictors of the response to treatment in patients with functional dyspepsia; a randomized, double-blind placebocontrolled crossover study. Dig Dis Sci 2004;49:6729. 27. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2003;(1):CD001960. 28. Talley NJ, Meineche-Schmidt V, Pare P, Duckworth M, Raisanen P, Pap A, et al. Efcacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies). Aliment Pharmacol Ther 1998;12:105565. 29. Blum AL, Arnold R, Stolte M, Fischer M, Koelz HR. Short course acid suppressive treatment for patients with functional dyspepsia: results depend on Helicobacter pylori status. The Frosch Study Group. Gut 2000;47:47380.

ing levels of acylated ghrelin and the subjective symptom score in FD patients. We also reported that, in patients with FD, and especially in those with dysmotility-like FD, plasma levels of ghrelin are signicantly increased,45 suggesting that compensatory secretion of ghrelin may be enhanced in patients with FD in order to normalize the impaired GI motility (dysmotility). As the secretion of ghrelin is continuous in patients with long-lasting and recurring clinical symptoms, plasma levels of ghrelin are persistently elevated. A synthetic GI peptide such as ghrelin or ghrelinresponsive agents might be used as a novel strategy for treating FD and similar functional GI disorders. Although the denition and diagnosis of FD are still controversial, the new classication system dened by the Rome III committee can be expected to lead to a better understanding of FD and to better practice in patient diagnosis and care. Although the diagnoses of general practitioners differed from those based entirely on the Rome II criteria,81 they might be improved in relation to the new diagnostic criteria based on the Rome III criteria, in which FD has been clearly subcategorized into PDS and EPS by excluding nonspecic-type dyspepsia. New persuasive evidence for the management of FD based on the new Rome III diagnostic criteria should be provided as soon as possible.

References
1. Drossman DA. The functional gastrointestinal disorders and the Rome II process. Gut 1999;45(Suppl 2):II15. 2. Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130:137790. 3. Bytzer P, Talley NJ. Dyspepsia. Ann Intern Med 2001;134:81522. 4. Talley NJ, Vakil N. Guidelines for the management of dyspepsia. Am J Gastroenterol 2005;100:232437. 5. Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:146679. 6. Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GN. Functional gastroduodenal disorders. Gut 1999; 45(Suppl II):3742. 7. Mearin F, Cucala M, Aspiroz F, Malagelada JF. The origin of symptoms of the braingut axis in functional dyspepsia. Gastroenterology 1991;101:9991006. 8. Peura DA, Kovacs TO, Metz DC, Siepman N, Pilmer BL, Talley NJ. Lansoprazole in the treatment of functional dyspepsia: two double-blind, randomized, placebo-controlled trials. Am J Med 2004;116:7408. 9. Tack J, Caenepeel P, Arts J, Lee KJ, Sifrim D, Janssens J. Prevalence of acid reux in functional dyspepsia and its association with symptom prole. Gut 2005;54:13706. 10. Carlsson R, Dent J, Bolling-Sternevald E, Johnsson F, Junghard O, Lauritsen K, et al. The usefulness of a structured questionnaire in the assessment of symptomatic gastroesophageal reux disease. Scand J Gastroenterol 1998;33:10239. 11. Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The efcacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology 2004; 127:132937.

522
30. Asaka M, Satoh K, Sugano K, Sugiyama T, Takahashi S, Fukuda Y, et al. Guidelines in the management of Helicobacter pylori infection in Japan. Helicobacter 2001;6:17786. 31. McColl K, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, et al. Symptomatic benet from eradicating Helicobacter pylori infection in patients with non-ulcer dyspepsia. N Engl J Med 1998;339:186974. 32. Blum AL, Talley NJ, OMorain C, van Zanten SV, Labenz J, Stolte M, et al. Lack of effect of treating Helicobacter pylori infection in patients with non-ulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect One Year after Treatment (OCAY) Study Group. N Engl J Med 1998;339:187581. 33. Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2003;(1):CD002096. 34. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia. A meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:3619. 35. Talley NJ, Vakil N, Ballard ED 2nd, Fennerty MB. Absence of benet of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 1999;341:110611. 36. Moayyedi P, Feltbower R, Brown J, Mason S, Mason J, Nathan J, et al. Effect of population screening and treatment for Helicobacter pylori on dyspepsia and quality of life in the community: a randomised controlled trial. Leeds HELP Study Group. Lancet 2000;355:16659. 37. Dhali GK, Garg PK, Sharma MP. Role of anti-Helicobacter pylori treatment in H. pylori-positive and cytoprotective drugs in H. pylori-negative, non-ulcer dyspepsia: results of a randomized, double-blind, controlled trial in Asian Indians. J Gastroenterol Hepatol 1999;14:5238. 38. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis. BMJ 1999;319:10404. 39. Moayyedi P, Soo S, Deeks J, Forman D, Mason J, Innes M, Delaney B. Systematic review and economic evaluation of Helicobacter pylori eradication treatment for non-ulcer dyspepsia. Dyspepsia Review Group. BMJ 2000;321:65964. 40. Moayyedi P, Soo S, Deeks J, Delaney B, Harris A, Innes M, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev 2006;(2):CD002096. 41. McNamara D, Buckley M, Gilvarry J, OMorain C. Does Helicobacter pylori eradication affect symptoms in non-ulcer dyspepsia: a 5-year follow-up study. Helicobacter 2002;7:31721. 42. Hsu PI, Lai KH, Lo GH, Tseng HH, Lo CC, Chen HC, et al. Risk factors for ulcer development in patients with non-ulcer dyspepsia: a prospective two year follow up study of 209 patients. Gut 2002;51:1520. 43. Suzuki H, Masaoka T, Sakai G, Ishii H, Hibi T. Improvement of gastrointestinal quality of life scores in cases of Helicobacter pyloripositive functional dyspepsia after successful eradication therapy. J Gastroenterol Hepatol 2005;20:165260. 44. Nishizawa T, Suzuki H, Nomoto Y, Masaoka T, Hosoda H, Mori M, et al. Enhanced plasma ghrelin levels in patients with functional dyspepsia. Aliment Pharmacol Ther Symp Ser 2006;2:(in press). 45. Svedlund J, Sjodin I, Dotevall G. GSRSa clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci 1988;33:12934. 46. Talley NJ. Therapeutic options in nonulcer dyspepsia. J Clin Gastroenterol 2001;32:28693. 47. Talley NJ, Verlinden M, Jones M. Can symptoms discriminate among those with delayed or normal gastric emptying in dysmotility-like dyspepsia? Am J Gastroenterol 2001;96:1422 8. 48. Dhir R, Richter JE. Erythromycin in the short- and long-term control of dyspepsia symptoms in patients with gastroparesis. J Clin Gastroenterol 2004;38:23742. 49. Tack J, Bisschops R, DeMarchi B. Causes and treatment of functional dyspepsia. Curr Gastroenterol Rep 2001;3:5038.

H. Suzuki et al.: Treatment of functional dyspepsia

50. Hallerback BI, Bommelaer G, Bredberg E, Campbell M, Hellblom M, Lauritsen K, et al. Dose nding study of mosapride in functional dyspepsia: a placebo-controlled, randomized study. Aliment Pharmacol Ther 2002;16:95967. 51. Otaka M, Jin M, Odashima M, Matsuhashi T, Wada I, Horikawa Y, et al. New strategy of therapy for functional dyspepsia using famotidine, mosapride and amitriptyline. Aliment Pharmacol Ther 2005;21(Suppl 2):426. 52. Kinoshita Y, Hashimoto T, Kawamura A, Yuki M, Amano K, Sato H, et al. Effects of famotidine, mosapride and tandospirone for treatment of functional dyspepsia. Aliment Pharmacol Ther 2005;21(Suppl 2):3741. 53. Hongo M. Initial approach and pharmacotherapy for functional dyspepsiaa large clinical trial in Japan. Gastroenterology 2006;130(4)(Suppl 2):A-506 (abstract). 54. Troncon LE, Bennett RJ, Ahluwalia NK, Thompson DG. Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994;35:32732. 55. Troncon LE, Thompson DG, Ahluwalia NK, Barlow J, Heggie L. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut 1995;37:1722. 56. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J. Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115:134652. 57. Hayakawa T, Arakawa T, Kase Y, Akiyama S, Ishige A, Takeda S, et al. Liu-jun-zi-tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp Clin Res 1999;25:2118. 58. Kido T, Nakai Y, Kase Y, Sakakibara I, Nomura M, Takeda S, et al. Effects of rikkunshi-to, a traditional Japanese medicine, on the delay of gastric emptying induced by N(G)-nitro-l-arginine. J Pharmacol Sci 2005;98:1617. 59. Tack J, Vos R, Janssens J, Salter J, Jauffret S, Vandeplassche G. Inuence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment Pharmacol Ther 2003;18:10317. 60. Riezzo G, Clemente C, Leo S, Russo F. The role of electrogastrography and gastrointestinal hormones in chemotherapy-related dyspeptic symptoms. J Gastroenterol 2005;40: 110715. 61. Tanum L, Malt UF. A new pharmacologic treatment of functional gastrointestinal disorder. A double-blind placebocontrolled study with mianserin. Scand J Gastroenterol 1996;31: 31825. 62. Mertz H, Fass R, Kodner A, Yan-Go F, Fullerton S, Mayer EA. Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia. Am J Gastroenterol 1998;93:1605. 63. Calvert EL, Houghton LA, Cooper P, Morris J, Whorwell PJ. Long-term improvement in functional dyspepsia using hypnotherapy. Gastroenterology 2002;123:177885. 64. Soo S, Moayyedi P, Deeks J, Delaney B, Lewis M, Forman D. Psychological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev 2005;(2):CD002301. 65. Hojo M, Miwa H, Yokoyama T, Ohkusa T, Nagahara A, Kawabe M, et al. Treatment of functional dyspepsia with antianxiety or antidepressive agents: systematic review. J Gastroenterol 2005;40:103642. 66. McHardy G, Atik M, Balart L, Sekinger D, McHardy R, Cradic H, et al. An evaluation of gastric hypothermia. Am J Dig Dis 1964;35:71725. 67. Deutsch EM. Relief of anxiety and related emotions in patients with gastrointestinal disorders. A double-blind controlled study. Am J Dig Dis 1971;16:10914. 68. Mine K, Kanazawa F, Hosoi M, Kinukawa N, Kubo C. Treating nonulcer dyspepsia considering both functional disorders of the digestive system and psychiatric conditions. Dig Dis Sci 1998;43: 12417.

H. Suzuki et al.: Treatment of functional dyspepsia

69. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:65660. 70. Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000;276:9058. 71. Mori M, Suzuki H, Masaoka T, Imaeda H, Nomoto Y, Hosoda H, et al. Intravenous ghrelin administration enhances gastric acid secretionevaluation using wireless pH capsule. Aliment Pharmacol Ther Symp Ser 2006;2:(in press). 72. Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, et al. Inuence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 2006;55:32733. 73. Suzuki H, Masaoka T, Hosoda H, Ota T, Minegishi Y, Nomura S, et al. Helicobacter pylori infection modies gastric and plasma ghrelin dynamics in Mongolian gerbils. Gut 2004;53:18794. 74. Abiko Y, Suzuki H, Masaoka T, Nomura S, Kurabayashi K, Hosoda H, et al. Enhanced plasma ghrelin levels in Helicobacter pylori-colonized, interleukin-1-receptor type 1-homozygous knockout (IL-1R1/) mice. World J Gastroenterol 2005;11: 414853. 75. Nishizawa T, Suzuki H, Masaoka T, Nomoto Y, Minegishi Y, Hosoda H, et al. Emotional stress enhanced ghrelin secretion from the stomach. J Clin Biochem Nutr 2006;38:337.

523
76. Suzuki H, Masaoka T, Hosoda H, Nomura S, Ohara T, Kangawa K, et al. Plasma ghrelin concentration correlates with the levels of serum pepsinogen I and pepsinogen I/II ratioa possible novel and non-invasive marker for gastric atrophy. Hepatogastroenterology 2004;51:124954. 77. Masaoka T, Suzuki H, Imaeda H, Hosoda H, Ohara T, Morishita T, et al. Long-term strict monitoring of plasma ghrelin and other serological markers of gastric diseases after Helicobacter pylori eradication. Hepatogastroenterology 2005;52:14. 78. Fukuhara S, Suzuki H, Masaoka T, Arakawa M, Hosoda H, Minegishi Y, et al. Enhanced ghrelin secretion in rats with cysteamine-induced duodenal ulcers. Am J Physiol Gastrointest Liver Physiol 2005;289:G13845. 79. Suzuki H, Masaoka T, Nomoto Y, Hosoda H, Mori M, Nishizawa T, et al. Increased levels of plasma ghrelin in peptic ulcer disease. Aliment Pharmacol Ther Symp Ser 2006;2:(in press). 80. Shinomiya T, Fukunaga M, Akamizu T, Irako T, Yokode M, Kangawa K, et al. Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol 2005;40:64853. 81. Farup PG, Vandvik PO, Aabakken L. How useful are the Rome II criteria for identication of upper gastrointestinal disorders in general practice? Scand J Gastroenterol 2005;40:12849.

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