Dyspepsia Clinical Trials, Diagnosis, and Treatment

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Dyspepsia

Dyspepsia (from the Greek "δυς-" (Dys-), meaning hard or difficult, and "πέψη" (Pepse), meaning digestion) is chronic or recurrent pain or discomfort centered in the upper abdomen Discomfort, in this context, includes mild pain, upper abdominal fullness and feeling full earlier than expected with eating. It can be accompanied by bloating, belching, nausea or heartburn. Heartburn is excluded from the definition of dyspesia in ICD 10, as it usually has a different cause and management pathway.

Many people get dyspepsia. It is often caused by lifestyle factors, such as smoking and diet, but there are some serious causes such as cancer of the stomach, peptic ulcer disease and some medications. When people have dyspepsia but no risk factors for any of the serious causes, it can be labeled undifferentiated dyspepsia and treated without further investigations. When people have been investigated for dyspepsia but no cause has been found it can be labeled as functional dyspepsia.

Current Research

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Investigation of Dyspepsia

People without risk factors for serious causes of dyspepsia usually do not need investigation beyond an office based clinical examination. However, people over the age 55 years and those with alarm features are usually investigated by esophagogastroduodenoscopy (EGD or OGD in Britain). In this painless investigation the esophagus, stomach and duodenum are examined through an endoscope passed down through the mouth. This will rule out peptic ulcer disease, medication related ulceration, malignancy and other rarer causes.

People under the age of 55 years with no alarm features do not need EGD but are considered for investigation for peptic ulcer disease caused by Helicobacter pylori infection. Investigation for H.pylori infection is usually performed when there is a moderate to high prevalence of this infection in the local community or the person with dyspepsia has other risk factors for H. pylori infection, related for example to ethnicity or immigration from a high-prevalence area. If infection is confirmed it can usually be eradicated by medication.

Medication related dyspepsia is usually related to Non-Steroidal Anti-inflammatory Drugs (NSAIDs) and can be complicated by bleeding or ulceration with perforation of the stomach wall.

Treatment of Functional Dyspepsia and Undifferentiated Dyspepsia

Treatment safely and successfully prescribed by doctors in Pakistan is a 10 day course and includes the following:

Risek 20mg capsules 1+1 for 10 days
Amoxil 500mg capsules 2+2 for 10 days
Claritek 500mg tablets 1+1 for 10 days
Ulsanic syrup 2+2+2 for 10 days

Functional and undifferentiated dyspepsia have similar treatments. Decisions around the use of drug therapy are difficult because trials included heartburn in the definition of dyspepsia. This led to the results favoring proton pump inhibitors (PPIs), which are questionably effective for the treatment of heartburn.

Traditional therapies used for this diagnosis include lifestyle modification, antacids, H2-receptor antagonists (H2-RAs), prokinetic agents, and antiflatulents. It is has been noted that one of the most frustrating aspects of treating functional dyspepsia is that these traditional agents have been shown to have little or no efficacy.

Antacids and sucralfate were found to be no better than placebo in a literature review. H2-RAs have been shown to have marked benefit in poor quality trials (30% relative risk reduction), but only a marginal benefit in good quality trials. Prokinetic agents would empirically seem to work well since delayed gastric emptying is considered a major pathophysiological mechanism in functional dyspepsia. They have been shown in a meta-analysis to produce a relative risk reduction of up to 50%, but the studies evaluated to come to this conclusion used the drug cisapride which has since been removed from the market (now only available as an investigational agent) due to serious adverse events such as torsades¬, and publication bias has been cited as a potential partial explanation for such a high benefit. Modern prokinetic agents such as metoclopramide, erythromycin and tegaserod have little or no established efficacy and often result in substantial side effects. Simethicone has been found to be of some value, as one trial suggests potential benefit over placebo and another shows equivalence with cisapride. So, with the somewhat recent advent of the proton pump inhibitor (PPI) class of medications, the question of whether these new agents are superior to traditional therapy has arisen.

A 2004 meta-analysis pooling data from three double-blind placebo-controlled studies found the multiple herbal extract Iberogast to be significantly more effective than placebo (p value = 0.001) at treating patients with functional dyspepsia through the targeting of multiple dyspeptic pathologies. This German-made phytopharmaceutical was found to be equivalent to cisapride and significantly superior to metochlopramide at reducing the symptoms of functional dyspepsia over a four week period. Retrospective surveillance of 40,961 children (12 years and under) found no serious side-effects.

Currently, PPIs are, depending on the specific drug, FDA indicated for erosive esophagitis, gastroesophageal reflux disease (GERD), Zollinger-Ellison syndrome, eradication of H. pylori, duodenal and gastric ulcers, and NSAID-induced ulcer healing and prevention, but not functional dyspepsia. There are, however, evidence-based guidelines and literature that evaluate the use of PPIs for this indication. A helpful chart summarizing the major trials is available from the functional dyspepsia guidelines published in the World Journal of Gastroenterology in 2006.

The CADET study was the first to compare a PPI (omeprazole 20mg daily) to both an H2-RA (ranitidine 150mg BID) as well as a prokinetic agent (cisapride 20mg BID) alongside placebo. The study evaluated these agents in patients at 4 weeks and 6 months and noted that omeprazole had a significantly better response at 6 months (31%) than cisapride (13%) or placebo (14%) (p = 0.001) while it was just above the cutoff for being statistically significantly better than ranitidine (21%) (p = 0.053). Omeprazole also showed a significant increase in quality of life scores over the other agents and placebo in all but one category measured (p = 0.01 to 0.05).

The ENCORE study, which was a follow-up of patients from the OPERA study, showed responders to omeprazole therapy had fewer clinic visits than non-responders (1.5 vs 2.0) over a three month period (p < 0.001)

(adapted from Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Dyspepsia)

Findings From Current Research

Functional Dyspepsia: Mechanisms of Symptom Generation and Appropriate Management of Patients

Authors: Camilleri M.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) Group, Mayo Clinic College of Medicine, Charlton 8-110, 200 First Street, SW, Rochester, MN 55905, USA.

With the exception of predominant heartburn, the management of upper abdominal symptoms not caused by an organic disorder remains a challenge. Systematic reviews of large trials show that suppressing acid secretion and eradicating Helicobacter pylori, prokinetics, and antidepressants have inconsistent effects on the treatment of functional dyspepsia. This inconsistent therapeutic efficacy has been attributed to the heterogeneity of patients, and the contribution of multiple mechanisms to development of symptoms. To achieve greater therapeutic efficacy, it may be necessary to target the therapeutic approach to a specific pathophysiology, such as impaired gastric emptying.

Journal: Gastroenterol Clin North Am. 2007 Sep;36(3):649-64.
Adapted from PubMed; click here to access full journal article.

Functional Dyspepsia: A New Rome III Paradigm

Authors: Halder SL, Talley NJ.

Nicholas J. Talley, MD, PhD Department of Internal Medicine, Mayo Clinic Jacksonville, 4500 San Pablo Road, Davis 6-72 E, Jacksonville, FL 32224, USA. talley.nicholas@mayo.edu.

Functional dyspepsia (FD) is a condition commonly seen in gastroenterological practice. With the introduction of Rome III criteria in 2006, a new approach for categorizing patients has been recommended. The diagnostic criteria suggest that meal-related and pain-predominant symptom groupings that presumably have distinct pathophysiologic mechanisms and potentially different therapeutic targets exist. The new classification is in the early stages of testing; in the meantime, the umbrella term of FD should continue to be utilized in clinical practice. Treatment of FD remains a major challenge. Unfortunately, most of the agents used in practice have limited or no evidence of efficacy, and the results typically are short-lived once therapy is ceased. Appropriate therapy currently is based on a consideration of putative pathophysiologic mechanisms. Testing for and eradicating Helicobacter pylori is a first-line strategy irrespective of the symptom pattern. In patients who have epigastric pain, antisecretory agents are recommended. Antacids, bismuth, and sucralfate seem to be no better than placebo. For meal-related symptoms such as postprandial fullness or early satiety, prokinetics may confer some benefit. However, few choices are available, and the efficacy for those drugs on the market is limited at best. Antidepressants are of uncertain efficacy but are widely used. Psychological therapies seem promising and may confer benefits on both pain and meal-related symptoms. Efficacy of complementary medicines has been suggested in controlled trials, but more data are needed. Emerging treatments include gastric fundus relaxors and visceral analgesics, although their application in FD is still in the preliminary stages.

Journal: Curr Treat Options Gastroenterol. 2007 Aug;10(4):259-72.
Adapted from PubMed; click here to access full journal article.

Randomized-Controlled Trial of Esomeprazole in Functional Dyspepsia Patients with Epigastric Pain or Burning: Does a 1-Week Trial of Acid Suppression Predict Symptom Response?

Authors: Talley NJ, Vakil N, Lauritsen K, van Zanten SV, Flook N, Bolling-Sternevald E, Persson T, Björck E, Lind T; STARS I Study Group.

Mayo Clinic College of Medicine, Rochester, MN, USA. talley.nicholas@mayo.edu

BACKGROUND: Early identification of true responders to acid suppression in functional dyspepsia patients with symptoms of epigastric pain or burning may enable clinicians to optimally tailor treatment. AIM: To evaluate whether a 1-w acid suppression trial is useful for identifying true responders in this population. METHODS: Patients (18-70 years) were randomized to either esomeprazole 40 mg q.d.s., b.d. or placebo for 1w, and then esomeprazole 40 mg q.d.s. or placebo for 7w. Epigastric pain and/or burning were recorded on a 4-point scale (0 = none, 3 = severe). Trial-week response was defined as symptom score sum < or = 1 on last 3d of therapy; response at 8w was symptom score sum < or = 1 over preceding 7d. RESULTS: 1-w response rates were 33% (199 of 597), 29% (188 of 629) and 23% (71 of 315) with esomeprazole q.d.s., esomeprazole b.d. and placebo, respectively (P = 0.002 for esomeprazole groups vs. placebo). At 8w, trial week sensitivity and specificity were 46% and 80%, respectively, for esomeprazole (40 or 80 mg), and 33% and 87%, respectively, for placebo. The positive and negative predictive values for esomeprazole were 60% and 69%. CONCLUSION: Response to a 1-w acid suppression trial is of limited use for predicting symptom response at 8w in patients with unexplained epigastric pain or burning.

Journal: Aliment Pharmacol Ther. 2007 Sep 1;26(5):673-82.
Adapted from PubMed; click here to access full journal article.

Non-Ulcer Dyspepsia and Duodenal Eosinophilia: An Adult Endoscopic Population-Based Case-Control Study

Authors: Talley NJ, Walker MM, Aro P, Ronkainen J, Storskrubb T, Hindley LA, Harmsen WS, Zinsmeister AR, Agréus L.

Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

BACKGROUND & AIMS: Functional abnormalities of the duodenum have been observed in non-ulcer dyspepsia. We aimed to identify whether eosinophils in the upper gastrointestinal tract are a biomarker for non-ulcer dyspepsia. METHODS: A random sample of an adult Swedish population (n = 1001; mean age, 54 y; 51% female) underwent upper endoscopy. Non-ulcer dyspepsia cases (n = 51, Rome II) and randomly selected controls (n = 48) were identified. Two blinded independent observers assessed the gastroduodenal eosinophil counts. Eosinophils were quantified by counting the number per 5 high-power fields at each of 5 sites (cardia, body, antrum, D1 duodenal bulb, and D2 second portion of duodenum), and total counts were summed over the 5 fields at each site. RESULTS: The odds ratio for non-ulcer dyspepsia (vs asymptomatic controls) in subjects with high duodenal bulb eosinophil counts (median, >/=22, relative to <22) was 11.7 (95% confidence interval, 3.9-34.9), adjusting for age, sex, and H pylori; similar results were observed in D2 (odds ratio = 7.3; 95% confidence interval, 2.9-18.1). A significant association with the number of eosinophil clusters was detected in the duodenum, with higher values in non-ulcer dyspepsia (P < .01). By immunostaining with major basic protein antibody in a subset of duodenal biopsy specimens, eosinophil degranulation was observed in non-ulcer dyspepsia (7 of 15 vs 0 of 5 controls; P = .11). Gastric eosinophil counts were overall not significantly increased in non-ulcer dyspepsia vs controls. Early satiety was associated with eosinophilia in D1 (P = .01) and D2 (P = .02), adjusting for age, sex, and H pylori. CONCLUSIONS: Duodenal eosinophilia may characterize a subset of adults with non-ulcer dyspepsia.

Journal: Clin Gastroenterol Hepatol. 2007 Oct;5(10):1175-83. Epub 2007 Aug 7.
Adapted from PubMed; click here to access full journal article.

The Effect of Low-Dose Aspirin on the Decreased Risk of Development of Dyspepsia and Gastrointestinal Ulcers Associated to Cyclooxygenase-2 Selective Inhibitors

Authors: Benito-Garcia E, Michaud K, Wolfe F.

Department of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA. ebenitogarcia@bioepi.com

OBJECTIVE: To evaluate the risk of gastrointestinal (GI) symptoms and ulcers associated to the use of low-dose aspirin (ASA) among patients with rheumatoid arthritis (RA) and osteoarthritis (OA) treated with cyclooxygenase-2 (COX-2) drugs, to clarify the controversy in the literature. METHODS: Using a longitudinal databank, a prospective study using Cox proportional hazards models was performed in patients receiving COX-2 therapy for RA or OA to examine the effect of ASA on GI events. In 4 separate analyses patients reported dyspeptic symptoms and GI ulcers at semiannual intervals for up to 3 years. Ulcers were validated by review of medical records. RESULTS: Among 4240 patients taking COX-2-specific inhibitors, with no ulcer at study start, the age- and sex-adjusted hazard ratios for the effect of ASA on the development of epigastric pain, heartburn, nausea, and ulcers, without these previous events, were 1.11 (95% CI 0.97-1.29), 1.00 (95% CI 0.88-1.15), 1.32 (95% CI 1.13-1.54), and 1.27 (95% CI 0.78-2.05). The use of a propensity score to account for the risk of ASA prescription showed an even lower effect of ASA among all GI variables. This risk occurs within the setting of no prior GI symptoms or GI events, and independently of the use of proton pump inhibitors, other GI drugs, other nonsteroidal antiinflammatory drugs, prednisone, or methotrexate. CONCLUSION: In actual practice, the use of low-dose ASA has a small effect on the risk of developing dyspeptic symptoms in a group of patients with rheumatic disease.

Journal: J Rheumatol. 2007 Aug;34(8):1765-9. Epub 2007 Jul 1.
Adapted from PubMed; click here to access full journal article.

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