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PRACTICAL THERAPEUTICS Drugs 45 (6): 918-930, 1993 0012-6667/93/0006-091/$06,50/0 Adis International Limited. All rights reserved DRU 1273 Functional Dyspepsia Current Treatment Recommendations Gerald Holtmann1 and Nicholas J, Talley2 1 2 Division of Gastroenterology, University of Essen, Essen, Federal Republic of Germany Division of Gastroenterology and Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, USA Contents 918 919 919 919 920 920 921 926 926 Summary Summary 1. Prevalence and Definition of Dyspepsia 2. Pathophysiological Basis of Functional Dyspepsia 3. Classification of Functional Dyspeptic Symptoms 4. Drug Treatment of Functional Dyspepsia 4.1 Methodological Limitations of Trials 4.2 Randomised Controlled Trials in Function Dyspepsia 5. Principles of Management of Functional Dyspepsia 6. Conclusion Symptoms of functional dyspepsia are frequent; the prevalence of dyspepsia (defined as pain or discomfort centred in the upper abdomen) in the general population approaches 25%. By definition, patients with functional dyspepsia do not have a structural'or biochemical explanation for their symptoms. Disorders of function (e.g. delayed gastric emptying) are detectable in a proportion of patients but remain poorly understood. Nevertheless, the current rationale for drug treatment is based on altering pathophysiological mechanisms which are believed to be associated with the development of symptoms. Although the placebo response rates approach 60%, prokinetics, acid-suppressing agents and bismuth-containing compounds have been shown to be significantly better than placebo in reducing symp toms. Antacids are widely used, but no controlled study has been able to demonstrate a significant benefit over placebo. The efficacy of sucralfate is uncertain. Rational guidelines on which drug should be used for a given patient are lacking, although approaches based on symptom profiles have been proposed; the duration of treatment needed to achieve long-lasting relief of symptoms is also poorly defined. Identifying optimal treatment for the individual patient, therefore, continues to be largely a trial and error process. Further re earch efforts are needed to elucidate the pathophysiological basis of functional dyspepsia so that specific therapy can be tailored to underlying pathophysiological disturbances. Drug Treatment of Functional Dyspepsia 1. Prevalence and Definition of Dyspepsia Dyspepsia is one of the most frequent health conditions encountered in the general population. Epidemiological studies have reported prevalence rates that approach 25% annually if dyspepsia is restricted to those who have recurrent upper abdominal symptoms, and heartburn alone is excluded (Talley el al. 1992). Nevertheless, most persons with dyspeptic symptoms do not seek medical attention. Functional (non-ulcer) dyspepsia is a heterogeneous disorder characterised by recurrent or chronic abdominal pain or discomfort centred in the upper abdomen. By definition, no organic disease such as peptic ulceration, gastric cancer, chronic pancreatitis or gastroesophageal reflux disease (GORD or GERD) can be identified as being responsible for the symptoms. Patients with functional dyspepsia often have many symptoms, and hence it has been suggested thai patients can be divided into subgroups based on the symptoms that predominate (Colin-Jones el al. 1988; Drossman et al. 1990; Talley el al. 199la). 2. Pathophysiological Basis of Functional Dyspepsia The pathophysiology of functional dyspepsia continues to be very poorly understood; this topic has been reviewed in detail recently (Holtmann & Goebell 1992; Talley & Phillips 1988; Talley et al. 199la). Disturbances which may be associated with the disorder include: (a) abnormal upper gastrointestinal motility and visceral perception that has been postulated to account for postprandial distress, nausea, bloating and early satiety; and (b) increased sensitivity to gastric acid with or without inflammation of the mucosa that may, in some cases, account for upper abdominal pain. Motility disturbances that have been observed in some, but not all, patients with functional dyspepsia include delayed gastric emptying and postprandial antral hypomotility (Malagelada 1991). Furthermore, some patienls wilh functional dyspepsia may have lower perception thresholds for 919 stimuli originating from the stomach based on balloon distension studies compared with asymptomatic controls. However, the relevance of these observations in the generation of symptoms still needs to.be determined (Talley & Phillips 1988). The relationship between dyspeptic symptoms and histological gastritis has remained controversial for years (Talley 1989). It is now accepted that chronic gastritis is usually a result of infection with Helicobacter pylori (Blaser 1990, 1992; Morris & Nicholson 1987). In previous studies, the prevalence rate of infection with H. pylori in patients with functional dyspepsia has approached 50% (Tytgat et al. 1991). However, because this infection is also common in asymptomatic persons (Dooley et al 1989), it remains unclear whether it plays a pathogenic role in the development of symptoms. Therefore, patients with dyspepsia and only histological gastritis are still considered to have functional dyspepsia (Talley et al. 199la). 3. Classification of Functional Dyspeptic Symptoms It is widely believed that patients with dyspepsia can be subdivided into subgroups based on the symptoms that predominate, but this also continues to be controversial (Colin-Jones 1988; Talley et al. 199la). Dyspepsia categories include 'ulcerlike', 'dysmotilily-Iike', 'reflux-like' and 'nonspecific' dyspepsia; it has been proposed that these subgroups reflect entities with different pathophysiologies. These are shown in table I. However, patients with true GORD are likely to account for most cases of so-called reflux-like dyspepsia, and such cases have probably often been included in therapeutic trials of functional dyspepsia. It is well known that patients with GORD respond to acidsuppressing measures which might at least partially account for the apparent positive effect of certain drugs in these studies. In general, we believe that patients with symptomatic GORD should not be given a label of functional dyspepsia. Unfortunately, only a minority of patienls have symptoms that fall into just one of the above mentioned categories; many patients have symptoms 920 that fall into two or more groups (Talley et al. 1992). There is also a substantial group of patients with symptoms that do not fit into any of the criteria shown in table I, and these are referred to as having nonspecific (or unspecified) dyspepsia. There is, in addition, a considerable overlap of functional dyspepsia with the symptoms of irritable bowel syndrome (IBS), and this applies to each of the symptom subgroups (Talley et al. 1992). Inclusion of patients with IBS may account for the lack of success of some of the therapeutic trials in functional dyspepsia. 4. Drug Treatment of Functional Dyspepsia Trials investigating drug therapy of patients with functional dyspepsia are of interest not only because they may identify effective treatments, but also because they may provide hints about the underlying pathophysiological mechanisms. 4.1 Methodological Limitations of Trials Many controlled and uncontrolled trials have been carried out assessing the effects of different drugs on the symptoms of functional dyspepsia. In Drugs 45 (6) 1993 general, most of these studies have had substantial methodological limitations (Talley 1991). First of all, there has usually been no carefully validated method utilised to assess improvement of symptoms. In the trials published to date, some studies have based improvement on a global assessment of symptoms only, but failed to take into account individual symptoms, or vice versa. In addition, some studies have been based on the symptom assessment of the treating physician, while others have relied on the patient's subjective assessment. Furthermore, most studies have failed to carefully assess symptom subgroups (e.g. ulcer-like or dysmotility-like), so the value of this classification is largely unknown. Unfortunately, quality of life or life satisfaction has generally been ignored. The relevance of this outcome variable can be illustrated by an example. An effective treatment that significantly reduces symptoms may on the other hand negatively affect the quality of life because the treatment has a major impact on lifestyle (e.g. frequent and inconvenient dosage schedule, or association with unpleasant side effects). Data on the outcomes of treatment in relation to cost (including costs of treatment, sick-leave days, etc.) are also lacking (Bate & Richardson 1993). Drug Treatment of Functional Dyspepsia Almost all studies have avoided a follow-up phase after completion of drug therapy, so the long term treatment outlook remains essentially unknown. A large number of studies have also lacked appropriate controls. In particular, a placebo group remains absolutely essential because otherwise there is no way of knowing the placebo responder rate, which approaches 60% in some studies (Delattre et al. 1985). A few experimental protocols have utilised multiple crossover designs where each patient is treated sequentially with placebo or drug; thus, each patient acts as his or her own control (Johannessen 1991), However, carryover effects from the preceding treatment may be a major problem that makes interpretation of such data difficult. Moreover, the generalisability of multiple 'n of 1' trials is questionable (Lewis 1991). Potential variability in the response rates in different populations have usually not been considered. In particular, if potent drugs are available as over-the-counter (OTC) medications, the proportion of patients who have undergone previous empirical treatment might be large, and only those not benefitting from medication (i.e. nonresponders) may have been included in the trials. Moreover, if patients are recruited only from tertiary care centres, the response rate to a drug may be much lower because these patients tend to comprise those with intractable symptoms. Whether racial or geographical influences affect the outcome of treatment is virtually unknown. Another drawback of numerous studies is the relatively small number of patients included; this becomes particularly important when a high placebo response is observed, because it may result in a considerable type II error (i.e. an under-powered study). 4.2 Randomised Controlled Trials in Functional Dyspepsia The present review has evaluated all published (primarily in peer reviewed journals), randomised, double-blind, placebo controlled studies that were identified by a Medline literature research for the period 1979 to 1992. Furthermore, major review articles (e.g. Dobrilla et al. 1989; Talley 1991; Veld- 921 huyzen van Zanten et al. 1989) were screened for published drug trials in patients with functional dyspepsia. Unpublished studies were not included because their quality remains questionable in the absence of careful peer review. Data from studies that lacked a placebo control or were presented as correspondence or abstracts are only reported where their information was of particular interest. 4.2.1 Prokinetic Agents Approximately 25 to 50% of patients with functional dyspepsia have objective evidence of gastroparesis, while less than 10% have small intestinal dysmotility (Malagelada 1991). Furthermore, a considerable proportion of patients with functional dyspepsia have symptoms compatible with a disturbance of gastrointestinal motility, although the correction between symptoms and motility derangements is weak (Malagelada 1991; Talley & Phillips 1988). Nevertheless, prokinetic drugs have been proposed as a rational treatment, particularly for patients with dysmotility-like symptoms (Talley et al. 199la). Two classes of prokinetic drugs are widely used, namely the dopaminergic receptor blockers and cisapride. Dopaminergic Receptor Blockers Dopaminergic receptors are primarily located in the proximal gastrointestinal tract; their blockade has stimulatory effects on upper gastrointestinal tract motility. Metoclppramide crosses the bloodbrain barrier and induces central antidopaminergic effects in 20% of patients. Thus, the use of metoclopramide is limited by unwanted CNS effects such as drowsiness, anxiety and extrapyramidal symptoms. These adverse effects are dose-related and usually reversible after discontinuation of treatment. Another adverse event seen during treatment with metoclopramide is the development of tardive dyskinesia which is rare, occurs predominantly in older patients, and is sometimes irreversible (Orme & Tallis 1984). Nevertheless, at dosages commonly used in the treatment of patients with functional dyspepsia, serious adverse effects, especially in younger patients, are uncommon. Based on the results of the available controlled 922 Drugs 45 (6) 1993 trials, we conclude that metoclopramide is probably efficacious in improving symptoms of functional dyspepsia (De Loose 1979; Johnson 1971; Perkel et al. 1979), but more data are needed. Domperidone is a peripherally acting dopamine antagonist (Champion 1988) that has now been extensively used in clinical practice; it does not cross the blood-brain barrier. Similar to metoclopramide, domperidone stimulates oesophageal, gastric and small intestinal motility (Weihrauch et al. 1979). In all but one study (Nagler & Miskovitz 1981), significant improvement of symptoms in patients with functional dyspepsia has been observed (table II). Furthermore, in a study of 10 female patients with functional dyspepsia, Bradette et al. (1991) showed that a fundic balloon elicited symptoms at lower volumes during placebo compared with domperidone treatment, suggesting that this drug may also alter visceral hypersensitivity. While domperidone is better than placebo in treating patients with functional dvspepsia, it is probably no more efficacious than metoclopramide (De Loose 1979). Cisapride Chemically related to metoclopramide is cisapride, a substituted piperdinyl benzamide. Cisapride facilitates cholinergic transmission in the myenteric plexus (Tonini et al. 1989), and this effect is thought to be at least partially mediated by the release of acetylcholine from postganglionic nerve endings in the myenteric plexus (Schuurkes et al. 1986). Whether this is a result of stimulation of serotoninergic (5-hydroxytryptamine) 5-HT4 receptors, or inhibition of inhibitory afferents is still unclear. Cisapride has been shown to increase lower oesophageal sphincter tone, increase oesophageal motility, and accelerate both gastric emptying and small intestinal transit (Ceccatelli et al. 1988; Gilbert et al. 1987; Madsen 1990; Smout et al. 1985). In clinical trials, 60 to 90% of patients with functional dyspepsia have had good to excellent global symptomatic responses to this drug; this is generally superior to placebo, although the proportion of placebo responses has been lower than expected in most of the trials (table II). A meta-analysis re- ported that prokinetic agents overall had a therapeutic success rate of approximately 50% over placebo (Dobrilla et al. 1989), although these pooled estimates have been questioned by others (Talley 1991; Veldhuyzen van Zanten et al. 1989). In contrast, despite a significant benefit in favour of cisapride compared with placebo after 2 weeks of treatment in dyspeptic patients with erosive prepyloric changes, this difference vanished Drug Treatment of Functional Dyspepsia during the re-evaluation after 4 weeks of treatment (Hauskcn & Berstad 1992). Similarly, in a small study of patients with recurrent right upper quadrant pain diagnosed as having the post-cholecystectomy syndrome (which in some cases appears to overlap with functional dyspepsia), cisapride was no more effective in relieving symptoms than placebo, despite the fact that the drug promoted biliary drainage (Farup et al. 1991). Whether cisapride is superior to standard doses of metoclopramide or domperidone remains controversial. Two studies (Corinaldesi ct al. 1987a; Verhaegen et al. 1987) did not detect significant differences, but one controlled study indicated that cisapride improved symptoms in patients whose symptoms did not improve after standard dosages of domperidone or metoclopramide (Van Outyre et al. 1990). However, further data are needed to confirm this finding. There is also debate whether or not combining different prokinetics is of clinical value. Recently, Tatsuta et al. (1992) compared the effects of cisapride alone with cisapride plus domperidone in patients with dyspeptic symptoms and delayed gastric emptying. In this study, the combination of cisapride and domperidone was more effective in reducing symptoms versus cisapride alone, even though only small numbers of patients were evaluated. Further studies are now required to clarify these issues. Other Prokinetic Agents Clebopride is a substituted benzamide that may also be a dopaminergic and serotoninergie antagonist. It has been compared with cisapride but not placebo in patients with functional dyspepsia, but it does not appear to offer any advantages over other prokinetic drugs (Sabbatini et al. 1991). Sulpiride, a dopaminergic antagonist, has been shown in one trial to be superior to placebo (Hui et al. 1986) but further data are lacking. 4.2.2 Antisecretory Drugs A large proportion of patients with functional dyspepsia have symptoms which traditionally have been considered to reflect an acid-related disorder, 923 namely ulcer-like dyspepsia. In addition, some patients with functional dyspepsia do have histologically documented inflammation of the gastric and duodenal mucosa, which it has been erroneously reasoned might heal if acid secretion were reduced even temporarily. Therefore, drugs aimed towards suppression of acid secretion have been frequently tested. Histamine H2-Receptor Antagonists Results on the efficacy of histamine H2-receptor antagonists, however, remain conflicting (table III). Whereas about half of the trials found a significant effect on dyspeptic symptoms, several studies were unable to detect differences between H2-receptor antagonists and placebo. The lack of a significant effect in these latter studies may in part be explained by the relatively small sample sizes and hence type II error. In addition, the heterogeneity of the study populations may have influenced the response to treatment. A limited meta-analysis has suggested that there is a 20% better therapeutic success rate with these drugs compared with placebo (Dobrilla et al. 1989). Both cimetidine (Johannessen et al. 1988, 1991, 1992) and ranitidine (Farup et al. 1991) have also been tested in multiple crossover trials in patients with functional dyspepsia. Results suggest that the active drug is modestly superior to placebo, and that those with ulcer-like dyspepsia or coexistent symptomatic GORD are most likely to respond. Pirenzepine The benefit of the selective muscarinic blocking agent pirenzepine remains controversial (Dal Monte et al. 1982; Hradsky & Wikander 1982; Smith et al. 1990;Talleyetal. 1986; Weberg & Berstad 1988). We conclude that, when these studies are all considered, pirenzepine is probably inferior to H2-receptor antagonists in managing functional dyspepsia. Besides a type II error due to the relatively small sample sizes in the negative studies, the substantially lower antisecretory potency of pirenzepine may help to explain these findings. 924 Drugs 45 (6) 1993 toms not responding to conventional acid-suppressing measures, a brief trial of a proton pump inhibitor may be justified. Proton Pump Inhibitors Proton pump inhibitors such as omeprazole have been introduced for the treatment of acid-related diseases in recent years. Clinical trials have commenced recently, but published data are not yet available regarding the efficacy of these compounds in functional dyspepsia. Theoretically, however, complete or near-complete inhibition of acid secretion could be of value in some patients with severe dyspeptic symptoms. On the other hand, because functional dyspepsia is a benign disorder, the uncritical use of H+,K+-ATPase inhibitors in this disorder must remain questionable until the long term safety of this class of drugs has been established in large populations. Nevertheless, in a limited number of patients with symp - 4.2.3 Sucralfate Sucralfate stimulates mucosal prostaglandin synthesis and has cytoprotective properties in experimental models, but has been tested in only two completed placebo controlled trials in patients with functional dyspepsia. One study (Kairaluoma et al. 1987) reported significant improvement of symptoms in 61 of 79 patients (77%) treated with sucralfate, compared with 40 of 72 (56%) in the placebo recipients. Interestingly, improvement of symptoms was better when endoscopy did not reveal erosions or macroscopic evidence of inflammation of the gastric mucosa. However, the response to treatment was independent of the histological grading of gastritis. Another study in 70 patients with functional dyspepsia who had erosions of the gastric and duodenal mucosa failed to detect a significant benefit of sucralfale over placebo (Skoubo-Kristensen et al. 1989). After 6 and 12 weeks, 80 and 83% of sucralfate recipients, respectively, reported improvement or complete disappearance of symptoms, compared with 73 and 79%, respectively, of placebo-treated patients. The lack of a significant difference may, therefore, be because of the large placebo response rate. Alternatively, patients with erosions may represent a group of patients who have different underlying pathophysiological mechanisms than patients without erosions. In an open trial, sucralfate Ig four times daily was compared with ranitidine 150mg twice daily in 100 dyspeptic patients (Misra et al. 1992). Here, global symptom improvement was significantly better in patients treated with sucralfate versus ranitidine (87 vs 64%) after four weeks. However, as there was no placebo group and it was an unblinded study, the findings are questionable. Sucralfate has also been compared with sulgicotide (sulglycotide), a sulphated glycopeptide that forms a protective barrier on eroded mucosal surfaces and stimulates mucus release, in two small double-blind, randomised trials (Barbara et al. 1990; Drug Treatment of Functional Dyspepsia Psilogenis et al. 1990). In both studies, symptoms improved to a similar extent in the treated patients, but again no placebo arm was included. Histological gastritis also similarly improved with both of these drugs but H. pylori status remained unchanged. 4.2:4 Antacids Antacids are frequently used, by patients with functional dyspepsia. However, of the four randomised, placebo controlled studies that have been reported to date (Gotthard et al. 1988; Nrrelund et al. 1980; Nyrwn et al 1986: Weberg & Berstad 1988), all have failed to show a significant effect of treatment, although there was improvement in both active and placebo treatment groups. One study compared an aluminum hydroxidecontaining antacid with sucralfate and placebo for 8 weeks in 45 patients with dyspepsia and who were considered to have duodenogastric reflux-induced bile gastritis, based on histology and scintigraphy (Masci et al. 1989). While the histological features improved to a greater degree during antacid treatment than with sucralfate or placebo, symptom responses were similar in all groups. However, the power of the study was very limited and it was not a blinded trial. 4.2.5 Treatment Aimed at Suppression and Eradication of H. pylori It is now accepted that chronic gastritis is usually caused by infection with H. pylori (Blaser 1990, 1992; Morris & Nicholson 1987; Talley 1989). In previous studies, the prevalence rate of infection with H. pylori in patients with functional dyspepsia has approached 50% (Loffeld et al. 1988; Rokkas et al. 1987), although infection is also common in asymptomatic persons (Dooley et al. 1989). It has nevertheless been postulated that H. pylori plays a pathogenic role in functional dyspepsia in at least a proportion of patients. If this holds true, symptoms should improve after eradication of H. pylori. Several randomised placebo controlled trials on the effects of bismuth-containing compounds have reported improvement of symptoms following active treatment Clearance of H. pylori and histo- 925 logical improvement has also been associated with a significant decrease in dyspeptic symptoms (Kang et al. 1990; Lambert et al. 1987; Rokkas et al. 1988). On the other hand, some trials have failed to detect a significant effect of bismuth-containing drugs on symptoms (Loffeld et al. 1989; McNulty et al. 1986). However, the methodological limitations of all these studies are considerable. Thus, improvement of syptoms has often been observed even in patients without H, pylori infection receiving active treatment, and in most patients eradication of H. pylori was not successful (Chiba et al. 1992; Dill et al, 1990). Any beneficial effect of bismuth, therefore, may be independent of the suppression or eradication of H. pylori. This is supported by observations from studies using antibiotics for suppression of H. pylori, which have not demonstrated a significant effect on symptoms (Glupczynski et al. 1988; Holcombe et al. 1992; Morgan et al. 1988), although the duration of treatment in some of these trials was possibly too short Hailey and Newsom (1984), in a small, randomised, placebo controlled, multi-crossover study, found that bismuth salicylate (bismuth subsalicylate) tended to relieve more episodes of dyspepsia and did so significantly faster than placebo, but carryover effects and gastritis were not evaluated. Only one study has reported the relationship between eradication of H. pylori and symptoms after 4 weeks of treatment. Symptoms improved simi-larly in those patients in whom H. pylon was or was not eradicated, but no placebo group was in-cluded, and this was not a randomised trial (Patch-ett et al. 1991). Recently, these authors have also reported preliminary data suggesting that one year after the end of eradication treatment, patients with persistent H. pylori had persistent symptoms, whereas patients without H. pylori were asymp-tomatic (O'Morain 1992). Randomised controlled trials are now urgently needed to address this issue (Talley et al. 1991b). In summary, the beneficial effect of eradication of H. pylori for dyspeptic symptoms has not yet been established; while bis-muth-containing agents probably have beneficial effects on dyspeptic symptoms, this might be in-dependent of effects on H. pylori. 926 Drugs 45 (6) 1993 4.2.6 Other Agents Several controlled and uncontrolled studies have been performed to assess the efficacy of other drugs. These include misoprostol (Hausken et al. 1990), pancreatic supplements (Kleveland et al. 1990), ursodeoxycholic acid (Pazzi et al. 1985; Tndury 1981), and antispasmodic drugs such as dicycloverine (dicyclomine) [Kagan et al. 1984; Stephens et al. 1988] or trimebutine (Walters et al. 1980). So far, these studies have not produced convincing evidence that such treatment strategies are better than placebo. 5. Principles of Management of Functional Dyspepsia If organic disease (e.g. peptic ulcer and oesophagitis) have been ruled out by endoscopy and other appropriate testing, additional diagnostic testing is unlikely to be positive. Reinvestigation should be avoided in most cases unless there is a change of symptoms suggesting the new onset of organic disease (e.g. severe weight loss, pain radiating through to the back). Patients should be strongly reassured about the absence of serious disease and should be informed about the nature of the disorder. In managing patients with functional dyspepsia, it is also useful to extract information about factors that preceded the onset of symptoms before drug treatment is considered. In particular, patients should be carefully questioned with respect to medication use, including nonsteroidal antiinflammatory drugs stopping these may significantly improve symptoms, Patients should be advised to avoid specific foods that clearly aggravate their symptoms (e.g. coffee, tea, alcohol). Obese patients should also be urged to normalise their weight, which is of particular help to patients who also have GORD. It is important to realise that some patients with functional dyspepsia are anxious, depressed or stressed, and these factors may be the major reason why the patient has sought counselling and treatment. Other patients have additional multisystem somatic symptoms, and display abnormal illness behaviour which may negatively affect management. A holistic approach alone is sufficient to effectively manage a considerable proportion of patients with functional dyspepsia. An important issue when considering drug treatment is the duration of symptoms. If symptoms have persisted for many years without affecting the quality of life, starting drug treatment is often unnecessary. In contrast, if symptoms are severely affecting quality of life, drug treatment should be considered. However, only some patients will respond, and many of those who do will have a recurrence of symptoms soon after stopping therapy. Thus, the optimal management of the patient with functional dyspepsia must take into account the intensity and duration of symptoms, and the impact of symptoms on quality of life. Numerous drugs are available to treat patients with functional dyspepsia as described above (section 4.2). The decision to start a medication has to keep in mind the potential risks of drug treatment; the risk: benefit ratio must be extremely low, because functional dyspepsia is a disease without any known mortality. The optimal duration of drug treatment is unknown, because no controlled data have evaluated the influence of duration of treatment on outcome. Until firm data are available, treatment should be given for as short a period as possible. It is common clinical practice to treat patients until symptoms have resolved and then discontinue medication. If symptoms do not respond after 2 to 4 weeks, then higher dosages or a different drug, or rarely a combination of medications, may be helpful. Many patients with functional dyspepsia have recurring symptoms, so intermittent treatment is often sufficient to achieve adequate control of the problem. 6. Conclusion Functional dyspepsia is a disorder with an extremely high prevalence in the general population. However, only a small proportion of subjects with functional dyspepsia require drug treatment. Medical treatment achieves at least partial relief of symptoms in the majority of patients. Because up to 60% of patients have considerable improvement of symptoms during placebo treatment (Talley & Drug Treatment of Functional Dyspepsia Phillips 1988), drugs which have not proven to be efficacious in controlled trials may often seem to be effective in relieving symptoms in clinical practice, which can be misleading. Still, we believe it is reasonable to take advantage of the placebo effect. It remains a challenge to select patients who will benefit from a particular medication and to determine the necessary duration of treatment. Because of the methodological difficulties listed above, and in particular the remarkable differences in the characteristics of patients included in the various trials, the clinical value of meta-analysis in this particular field currently appears to be limited. It is still widely believed that patients with dyspepsia can be subdivided into subgroups based on the symptoms that predominate (Colin-Jones et al. 1988; Talley et al. 199la). However, there are no convincing data indicating that such a symptomoriented classification identifies responders to a particular type of treatment. Still, in clinical practice it is not unreasonable to use acid-suppressive treatment or bismuth-containing drugs as first-line treatment for patients with ulcer-like symptoms. and prokinetic therapy for patients with dysmotility-like symptoms. Until the pathophysiological basis of this disorder has been further elucidated, empirical treatment will continue to dominate clinical practice. Acknowledgements Supported in part by a grant from Deutsche Forschungsgemeinschaft, grant number Ho 1193/3-1 and by the Mayo Foundation. References Agorastos I, Zissis NP, Kaprinis I. Goulis G. Double-blind evaluation of domperidone in acute vomiting and dyspeptic disorders. Journal of International Medical Research 9: 143-147, 1981 Arts E. Anthoni H, de Roy G, D'HolIander J, Verhaegen H. Dompendone in the treatment of dyspepsia: a double-blind placebo-controlled study. Journal of International Medical Research 7: 158-161, 1979 Barbara L, Biasco G, Capurso L, Dobrilla G, Lalli A, ct al. Effects of sucralfate and suiglycotide treatment on active gastritis and Helicobacter pylori colonization of the gastric mucosa in nonulcer dyspepsia. American Journal of Gastroenterology 85: 11091113, 1990 927 Bate CM, Richardson PDI. Clinical and economic factors in selection of drugs for gastroesophageal reflux disease. PharmacoEconomics 3: 94-99, 1993 Bekhti A. Rutgecrts L. Dompcridonc in the treatment of functional dyspepsia in patients with delayed gastric emptying. Postgraduate Medical Journal 55 (Suppl.l): 30-32, 1979 Berndtsen F, Dano P, Guldhammer B, Remvig L, Krogsoe O. Cimitidine behandling af nontgennegativ dyspepsi. Ugeskrift foer Laeger 145: 3090-3093, 1983 Blaser MJ. Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation. Gastroenterology 102: 720-727, 1992 Blaser MJ. Helicobacter pylori and the pathogenesis of gastroduodcnal inflammation. Journal of Infectious Diseases 161: 626633, 1990 Bradette M, Pare P, Douville P, Morin A. Visceral perception in health and functional dyspepsia. Crossover study of gastric distension with placebo and domperidone. Digestive Diseases and Sciences 36: 52-58, 1991 Ceccatelli P, Janssens J, Vantrapppen G, Cucchiara S. Cisapridc restores the decreased lower oesophageal sphineter pressure in reflux patients. Gut 29: 631-635, 1988 Champion MC. Domperidone. General Pharmacology 19: 499505, 1988 Chiba N, Rao BV, Rademaker JW, Hunt RW. Meta-analysis of, the efficacy of antibiotic therapy in eradicating Helicobacter pylori. American Journal of Gastroenterology 87: 1716-1727, 1992 Colin-Jones DG, Bloom B, Bodemar G, Crean G, Freston J, et al. Management of dyspepsia: report of a working party. Lancet 1: 576-579, 1988 Corinaldcsi R, Raiti C, Stanghellini V, Moriediti N, Rea E, et al. Comparative effects of oral cisapride and metoclopramide on gastric emptying of solids and symptoms in patients with functional dyspepsia and gastroparesis. Current Therapeutic Research 42: 428-435, 1987a Corinaldcsi R, Stanghellini V, Raiti C, Rea E, Salgemini R, et al. Effect of chronic administration of cisapride on gastric emptying of a solid meal and on dyspeptic symptoms in patients with idiopathic gastroparesis. Gut 28: 300-305, 1987b Coutant G. Francois I, DeNutte N, DeCock G, Borgers P, et al. Dose response study of cisapride in the management of nonulcer dyspepsia. Progress in Medicine 43 (Suppl. 1): 91-96, 1987 Creytens G. Effect of the non-antidopaminergic drug cisapride on postprandial nausea. Current Therapeutic Research 36: 10631069, 1984 Dal Monte PR, D'Imperio N, Accardo P. Daniotti S. Pirenzepine in non-ulcer dyspepsia. A double-blind, placebo controlled trial. Scandinavian Journal of Gastroenterology 17 (Suppl. 72): 247250, 1982 Davis RH, Clench MH, Mathias JR. Effects of domperidone in patients with chronic unexplained upper gastrointestinal symptoms: a double-blind, placebo-controlled study. Digestive Diseases and Sciences 33: 1505-1511, 1988 Delattrc M, Malesky M, Prin/ie A. Symptomatic treatment of non-ulcer dyspepsia with cimetidine. Current Therapeutic Research 37: 980-991, 1985 De Loose F. Domperidone in chronic dyspepsia: a pilot open study and a multicentre general practice crossover comparison with metoclopramide and placebo. Pharmatherapeutica 2: 140146, 1979 De Nutte N, Van Ganse W, Wetterbulghe M, Defrance P. Relief of epigastric pain in non ulcer dyspepsia: controlled trial of the promotility drug cisapride. Clinical Therapeutics 11: 62-68, 1989 Deruyttere M, Milo R, Creytens G, Goethals C, Bourgeois E, et al. Therapy of chronic functional dyspepsia: multicenter crossover study of cisapride and placebo. Progress in Medicine 43 (Suppl. 1): 61-68, 1987 Dill S, Payne-James JJ, Misiewicz JJ, Grimbie GK, McSwiggan 928 D, et ai. Evaluation of the 13C-urea breath test in the detection of Helicobacter pylori and in monitoring the effect of tripotassium dicitrobismuthate in non ulcer dyspepsia. Gut 31: 12371241, 1990 Dobrilla G, Comberlato M, Steele A, Vallaperta P. Drug treatment of functional dyspepsia. A mcta-analysis of randomized controlled trials. Journal of Clinical Gastroenterology 11: 169177, 1989 Dooley CP, Cohen H, Fitzgibbons P, Bauer M, Appleman MD, et al. Prevalence of Helicobacter pylori and histologic gastritis in asymptomatic persons. New England Journal of Medicine 321: 1562-1566, 1989 Drossman DA, Thompson WG, Talley, NJ, Funch-Jensen P, Janssens J, et al. Identification of subgroups of functional gastrointestinal disorders. Gastroenterology International 3: 159172, 1990 Englert W, Schlich D. A double-blind crossover trial of domperidone in chronic postprandial dyspepsia. Postgraduate Medical Journal 55 (Suppl. 1): 28-29, 1979 Farup PG, Larsen S, Ulshagen K, Osnes M. Ranitidime for nonulcer dyspepsia. A clinical study of the symptomatic effect of ranitidine and a classification and characterization of the responders to treatment. Scandinavian Journal of Gastroenterology 26: 1209-1216, 1991 Farup PG, Tjora S, Tholfsen JK. Effect of cisapride on symptoms and biliary drainage in patients with postcholecystectomy syndrome. Scandinavian Journal of Gastroenterology 26: 945-950, 1991 Francois I, De Nutte N. Non-ulcer dyspepsia. Effect of the gastrointestinal prokinetic drug cisapride. Current Therapeutic Research 41: 891-898, 1987 Gilbert RJ, Dodds WJ, Kahrilas PJ, Hogan WJ, Lipman S. Effect of cisapride, a new prokinetic agent, on esophageal motor function. Digestive Diseases and Sciences 32: 1331-1336, 1987 Glupezynski Y, Burette A, Labbe M, Deprez C De Reuck M, et al. Campylobacter pylori-associated gastritis: a double-blind placebo-controlled trial with amoxycillin. American Journal of Gastroenterology 83: 365-372, 1988 Goethals C, Van de Mierop L. Cisapride in the treatment of chronic functional dyspepsia. Results of a double-blind, placebo-controlled, crossover study. Current Therapeutic Research 42: 261267, 1987 Gotthard R, Bodemar G, Brodin U, Jonsson K-A. Treatment with cimetidine, antacid or placebo in patients with dyspepsia of unknown origin. Scandinavian Journal of Gastroenterology 23: 7-18, 1988 Haarmann K, Lebkuchner F, Widmann A, Kief W, Esslinger M. A double-blind study of domperidone in the symptomatic treatment of chronic postprandial upper gastrointestinal distress. Postgraduate Medical Journal 55 (Suppl. 1): 24-27, 1979 Hailey FJ, Newsom JG. Evaluation of bismuth subsalicylate in relieving symptoms of indigestion. Archives of Internal Medicine 144:^269-272, 1984 Hannon R. Efficacy of cisapride in patients with non-ulcer dyspepsia. A placebo-controlled study. Current Therapeutic Research 42: 814-822, 1987 Hausken T, Berstad A. Cisapride treatment of pateints with nonulcer dyspepsia and erosive prepylorioc changes. A double placebo controlled trial. Scandinavian Journal of Gastroenterology 27: 213-217, 1992 Hausken T, Stene-Larsen G, Lange O, Aronsen O, Nerdrum T, et al. Misoprostol treatment exacerbates abdominal discomfort in patients with non-ulcer dyspepsia and erosive prepyloric changes. Scandinavian Journal of Gastroenterology 25; 10281033, 1990 Holcombe C, Thorn C, Kaluba J, Lucas SB. Helicobacter pylori clearance in the treatment of non-ulcer dyspepsia. Alimentary Pharmacology and Therapeutics 6: 119-123 1992 Drugs 45 (6) 1993 Holtmann G, Goebell, H. Ursachen der funktionellen Dyspepsie. Deutsche Medizinische Wochenschrift 117: 1029-1034, 1992 Hradsky M, Wikander M. Effect of pirenzepine in the treatment of non-ulcer dyspepsia. A double-blind study. Scandinavian Journal of Gastroenterology 17 (Suppl. 72): 251-254, 1982 Hui WM, Lam SK, Lok ASF, Ng MMT, Wong KL, et al. Sulpiride improves functional dyspepsia: a double-blind controlled study. Journal of Gaslroenlerology and Hepatology 1: 391-399, 1986 Jian R, Ducrot F, Ruskone A, Chau.ssade S, Ram baud JC, et al, Symptomatic radionuclide and therapeutic assessment of chronic idiopathic dyspepsia: a double-blind placebo-controlled evaluation of cisapride. Digestive Diseases and Sciences 34: 657-664, 1989 Johannessen T. Controlled trials in single subjects. 1. Value in clinical medicine. British Medical Journal 303: 173-174, 1991 Johannessen T, Føjsne U, Cleveland M, Halvorsen T, Kristenson P, et al. Cimetidine responders in non-ulcer dyspepsia. Scandinavian Journal of Gastroenterology 23: 327-336, 1988 Johannessen T, Kristensen P, Petersen H, Fosstvedt D, Løge I, et al. The symptomatic effect of 1-day treatment periods with cimetidine in dyspepsia. Combined results from randomized, controlled, single-subject trials. Scandinavian Journal of Gastroenterology 26: 974-980, 1991 Johannessen T, Petersen H, Kristensen P, Fosstvedt D, Kleveland PM, et al. Cimetidine on-demand in dyspepsia. Experience with randomized controlled single-subject trials. Scandinavian Journal of Gastroenterology 27: 189-195, 1992 Johnson AG. Controlled trial of metoclopramide in the treatment of flatulent dyspepsia. British Medical Journal 2: 25-26, 1971 Kagan G, Huddlestone L, Wolstencroft P. Comparison of diclomine with antacid and without antacid in dyspepsia. Journal of International Medical Research 12: 174-178, 1984 Kairaluoma MI, Hentilae R, Alavaikko M, Kellosalo J, Stabilber M, et al. Sucralfate versus placebo in treatment of non-ulcer dyspepsia. American Journal of Medicine 83 (Suppl. 313): 5155, 1987 Kang JY, Tay HH, Wee A, Guan R, Math MV, et al. Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double-blind, placebo-controlled study. Gut 31: 476-480, 1990 Kelbaek H, Linde J, Eriksen J, Munkgaard S, Moesgaard F, et al Controlled clinical trial of treatment with cimetidine for nonulcer dyspepsia. Acta Medica Scandinavica 217: 281-287, 1985 Kleveland PM, Johannessen T, Kristensen P, Lge I, Sandbakken P, et al. Effect of pancreatic enzymes in non-ulcer dyspepsia Scandinavian vian journal of Gastroenterology 25: 298-301, 1990 Lambert JR, Borromeo M, Korman MG, Hansky J. Role of Campylobacter pyloridis in non-ulcer dyspepsia - a randomized controlled trial. Gastroenterology 92: 1488, 1987 Lance P, Wastell C, Schiller KFR. A controlled trial of cimetidini for the treatment of non-ulcer dyspepsia. Journal of Clinical Gastroenterology 8: 414-418, 1986 Lewis JA. Controlled trials in single subjects. 2. Limitations of use. British Medical Journal 303: 175-176, 1991 Loffeld RJLF, Potters HVPJ, Arends JN, Stobberingh E, Flendrig JA, et al. Campylobacter associated gastritis in patients with non-ulcer dyspepsia. Journal of Clinical Pathology 41: 85-88 1988 Loffeld RJLF, Potters HVPJ, Stobberingh E, Flendrig JA, Van Spreeuwel JP, et al. Campylobacter-associated gastritis in patients with non-ulcer dyspepsia: a double-blind, placebocontrolled trial with colloidal bismuth subcitrate. Gut 30: 12061212, 1989 Madsen JL. Effects of cisapride on gastrointestinal transit in healthy humans. Digestive Diseases and Sciences 35: 1500-1504, 1990 Malagelada JR. Gastrointestinal motor disturbances in functional dyspepsia. Scandinavian Journal of Gastroenterology 26 (Suppl 182): 29-32, 1991 Drug Treatment of Functional Dyspepsia Masci E, Bierti L, Tcstoni PA, Fonti L, Passarctti S, et al. Aluminum-hydroxidc-containing antacids and sucralfatc in the treatment of reflux gastritis in patients not previously sub mittcd to gastric surgery; comparison with placebo. Current Therapeutic Research 46: 193-199, 1989 McNulty CAM, Gearty JC, Crump B, Davis M, Donovan IA, et al. Campylobacter pyloridis and associated gastritis: investigator blind, placebo-controlled trial of bismuth salicylate and erythromycin ethylsuccinate. British Medical Journal 293: 645649, 1986 Milo R. Non-cholinergic, non-antidopaminergic treatment of chronic digestive symptoms suggestive of a motility disorder: a two-step pilot evaluation of cisapride. Current Therapeutic Research 36: 1053-1062, 1984 Misra SP, Dwivcdi Mt Misra V, Agarwal SK. Sucralfate versus ranitidine in non-ulcer dyspepsia: results of a prospective randomized, open, controlled trial. Indian Journal of Gastroenterology 11: 7-8, 1992 Morgan D, Kraft W, Bender M, Pearson A. Nitrofurans treatment of gastritis associated with campylobacter pylori. Gastroenterology 95: 1178-1184, 1988 Morris A, Nicholson G. ingestion of Campylobacter pyloridis causing gastritis and raised fasting pH. American Journal of Gastroenlerology 82: 192-199, 1987 Nagler J, Miskovitz P. Clinical evaluation of domperidone in the treatment of chronic postprandial idiopathic upper gastrointestinal distress. American Journal of Gastroentcrology 76: 495499, 1981 Nesland AA, Berstad A. Effect of cimetidine in patients with nonulcer dyspepsia and erosive prepyloric changes. Scandinavian Journal of Gastroenterology 20: 629-635, 1985 Norrelund N, Helles A, Schmiegelow M. Ukarakätristisk dyspepsi i almen praksis. En kontrolleret undersøgelse med et antaci dum (Alminox®). Ugeskrift foer Laeger 142: 1750-1753, 1980 Nyérn O, Adami H-O, Bates S, Bergstrom R, Gustavsson S, et al Absence of therapeutic benefit from antacids or cimetidine in non-ulcer dyspepsia. New England Journal of Medicine 314. 339-343, 1986 Nyérn O Functional dyspepsia-a disorder of the stomach? Gustavssons et al. (Eds) The stomach, pp. 385-415. Longman Group Ltd., New York, 1992 Olubuyide IO, Ayoola EA, Okubanjo AO, Atoba MA. Non-ulcer dyspepsia in Nigerians clinical and therapeutic results. Scandinavian Journal of Gastroenterology 21 (Suppl. 124): 83-87, 1986 O'Morain. Helicobacter pylori and non-ulcer dyspepsia. Correspondence. Gastroenterology 103: 341, 1992 Orme MLE, Tallis RC. Metoclopramidc and tardive dyskinesia in the elderly. British Medical Journal 289: 397-298, 1984 Patchettt S, Beattie S, Leen E, Keane C, O'Morain C. Helicobacter pylori and non-ulcer dyspepsia. British Medical Journal 303: 1238-1240, 1991 Pazzi P. Stabellini G, Trevisani L, Arlotti A, Massari M, et al. Effect of ursodeoxycholic acid (UDCA) on 'biliary dyspepsia' in patients without gallstones. Current Therapeutic Research 37: 685-694, 1985 Perkel MS, Moore C, Hersh T, Davidson ED. Metoclopramide therapy in patients with delayed gastric emptying. A randomized, double-blind study. Digestive Diseases and Sciences 24: 662-666, 1979 Psilogenis M, Nazzari M, Ferrari PA. A multicenter double-blind study of sulglycotide versus sucralfate in nonulcer dyspepsia. International Journal of Clinical Pharmacology Therapy and Toxicology 28: 369-74, 1990 Rokkas T, Pursey C, Uzoechina E, Dorrington L, Simmons NA, et al. Campylobacter pylori and non-ulcer dyspepsia. American Journal of Gastroenterology 82: 1149-1152, 1987 Rokkas T, Pursey C, Uzoechina E, Dorrington L, Simmons NA, et al. Non-ulcer dyspepsia and short-term 'De-Nol' therapy: a 929 placebo controlled trial with particular reference to the role of Campylobacter pylori. Gut 29: 1386-1391. 1988 Rösch W. Cisapride in non-ulcer dyspepsia. Results of a placebocontrolled trial. Scandinavian Journal of Gastroenterology 22: 161-164, 1987 Sabbatini F, Minieri M, Manzi G, Piai G, D'Angelo V, et al. Clinical efficacy and safety of cisapride and clebopride in the management of chronic functional dyspepsia: a double-blind, randomized study. Italian Journal of Gastroenterology 23: 14, 1991 Sarin SK, Sharma P, Chawla YK, Gopinath P, Nundy S. Clinical trial on the effect of domperidone on non-ulcer dyspepsia. Indian Journal of Medical Research 83: 623-28, 1986 Saundcrs JHB, Oliver RJ, Higson DL. Dyspepsia: incidence of non-ulcer disease in a controlled trial of ranitidine in general practice. British Medical Journal 292: 665-668, 1986 Schuurkes JAJ, Helsen LFM, Ghoos ECR, Eelen JGM, Van Nueten JM. Stimulation of gastroduodenal motor activity: dopaminergic and cholinergic modulation. Drug Development Research 8: 233-241, 1986 Singal AK, Kumar A, Broor SL. Cimetidine in the treatment of non-ulcer dyspepsia: results of a randomized double-blind, placebo-controlled study. Current Medical Research and Opinion 11: 390-397, 1989 Skoubo-Kristensen E, Funch-Jensen P, Kruse A, Hanberg-Sørensen F, Amdrup E. Controlled clinicrl trial with sucralfate in the treatment of macroscopic gastritis. Scandinavian Journal of Gastroenterology 24: 716-720, 1989 Smith PM. Trouehton AH, Gleeson F, Walters J, McCarthy CF. Pirenzpine in non-ulcer dyspepsia: a double-blind placebo controlled trial. Journal of International Medical Research 18: 1620, 1990 Smout AJPM, Bogaard JW, Grade AC, Ten Thife UJ, Akkermans WA, et al. Effects of cisapride, a new gastrointestinal prokinetic substance, on interdigcstive and postprandial motor activity of the distal esophagus in man. Gut 26: 246-251, 1985 Stephens CJM, Lever L, Hoare AM. Dicyclomine for idiopathic dyspepsia. Lancet 1: 1004, 1988 Talley NJ, McNeil D, Hayden A, Piper DW. Randomized, doubleblind, placebo-controlled crossover trial of cimetidine and pircnzepinc in nonulcer dyspepsia. Gastroentcrology 91: 149-156, 1986 Talley NJ, Phillips SF. Non-ulcer dyspepsia: potential causes and pathophysiology. Annals of Internal Medicine 108: 865-879, 1988 Talley NJ. Chronic (non-specific) gastritis. Digestive Diseases 7: 61-75, 1989 Talley NJ, Colin-Jones D, Koch KL, Koch M, Nyrén O, et al. Functional dyspepsia: a classification with guidelines for diagnosis and management. Gastroentcrology International 4: 145160, 199 la Talley NJ, Ormand JE, Carpenter HA, Phillips SF. Triple therapy for Helicobacter pylori in non-ulcer dyspepsia. American Journal of Gastroenterology 86: 121-123, I991b Talley NJ. Drug treatment of functional dyspepsia. Scandinavian Journal of Gastroenterology 26 (Suppl. 182): 47-60, 1991 Talley NJ, Zinsmeister, AR, Schleck CD, Melton III LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 102: 1259-1268, 1992 Tatsuta M, lishi H, Nakaizumi A, Okuda S. Effect of treatment with cisapride alone or in combination with domperidone on gastric emptying and gastrointestinal symptoms in dyspeptic patients. Alimentary Pharmacology and Therapeutics 6: 221228, 1992 Testoni PA, Bagnolo F, Fanti L, Passaretti S, Titobello A. Long term oral cisapride interdigestive antroduodenal motility in dyspeptic patients. Gut 31: 286-290, 1990 Töndury GD. Die Behandlung eines Syndroms von dyspep - 930 tischen Beschwerden mit Ursodesoxycholsäure. Schweizerische Medizinische. Rundschau 70: 969-973, 1981 Tonini M, Galligan JJ, North RA. Effects of cisapride on cholinergic neurotransmission and propulsive motility in the guinea pig ileum. Gastroenterology 96: 1257-1264, 1989 Tytgat GNJ, Noach LA, Rauws EAJ. Is gastroduodenitis a cause of chronic dyspepsia? Scandinavian Journal of Gastroenterology 26 (Suppl. 182): 33-39, 1991 Van de Mierop L, Rutgeerts L, Van den Langenbergh B, Staessen A, Oral domperidone in chronic postprandial dyspepsia. A double-blind placebo-controlled evaluation. Digestion 19: 244250, 1979 Van Ganse W, Reyntjens A. Clinical evaluation of cisapride in postprandial dyspepsia. Progress in Medicine 43 (Suppl. 1): 7781, 1987 Van Ganse W, Van Damme L, Van de Mierop L, Deruyttere M, Lauwers W, et al. Chronic dyspepsia: double-blind treatment with domperidone (R33812) or a placebo. A multi-centre therapeutic evaluation. Current Therapeutic Research 23: 695-701, 1978 Van Outyre M, van Egham P, Reyntjens A. Cisapride in the treatment of non-ulcer dyspepsia patients, unresponsive to domperidone or metoclopramide: a multicentre, double-blind, placebo-controlled study. World Congresses of Gastroenterology, Sydney, August 1990. Abstract FP628, 1990. Drugs 45 (6) 1993 Veldhuyzen van Zanten SJO, Tytgat KMAJ. Jaii S, Goodacre RI., Hunt RH. Can gastritis symptoms be evaluated in clinical trials An overview or treatment of gastritis, non-ulcer dyspepsia and Campylobacter associated gastritis. Journal of Clinical Gastroenterology 11: 496-501, 1989 Verhaegen H, de Cree J, Leempoels J. Treatment of chronic dyspepsia with cisapride and domperidone. Acta Therapeutica 13: 385-394, 1987 Walters JM, Crean P, McCarthy CF. Trimebutine, a new antispasmodic in the treatment of dyspepsia. Irish Journal of Medicine 73: 380-381, 1980 Weberg R, Berstad A. Low-dose antacids and pircnzepine in the treatment of patients with non-ulcer dyspepsia and erosive prepyloric changes. A randomized, double-blind, placebo-controlled trial. Scandinavian Journal of Gastroenterology 23: 237243, 1988 Weihrauch TR, Forster CRF, Krieglstein J. Evaluation of the effect of domperidone on human esophageal and gastroduodenal motility by intraluminal manometry. Postgraduate Medical Journal 55: 7, 1979 Correspondence and reprints: Dr Nicholas J. Talley, Associate Professor of Medicine, Gastroenterology Unit, Mayo Clinic and Foundation Rochester, MN 55905, USA.