Clinical Review

Managing Dyspepsia

Clinician Reviews. 2015 June;25(6):350-357

References

1. Shaib Y, El-Serag HB. The prevalence and risk factors of functional dyspepsia in a multiethnic population in the United States. Am J Gastroenterol. 2004;99:2210-2216.

2. Talley NJ. Dyspepsia: management guidelines for the millennium. Gut. 2002;50(suppl 4):iv72–iv78.

3. Harmon RC, Peura DA. Evaluation and management of dyspepsia. Therap Adv Gastroenterol. 2010;3:87–98.

4. Bazaldua OV, Schneider FD. Evaluation and management of dyspepsia. Am Fam Physician. 1999;60:1773-1784.

5. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology. 2006;130:1466-1479.

6. Haag S, Talley NJ, Holtmann G. Symptom patterns in functional dyspepsia and irritable bowel syndrome: relationship to disturbances in gastric emptying and response to a nutrient challenge in consulters and non-consulters. Gut. 2004;53:1445-1451.

7. Malfertheiner P, Megraud F, O’Morain CA, et al; European Helicobacter Study Group. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus Report. Gut. 2012;61:646-664.

8. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology. 2005;129:1756-1780.

9. Moayyedi P, Axon AT. The usefulness of the likelihood ratio in the diagnosis of dyspepsia and gastroesophageal reflux disease. Am J Gastroenterol. 1999;94:3122-3125.

10. McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med. 2010;362:1597-1604.

11. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al; American Gastroenterological Association. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135:1383-1391.

12. Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori Infection. Am J Gastroenterol. 2007;102:1808-1825.

13. Moayyedi P, Talley NJ, Fennerty MB, et al. Can the clinical history distinguish between organic and functional dyspepsia? JAMA. 2006;295:1566-1576.

14. Eslick GD, Howell SC, Hammer J, et al. Empirically derived symptom sub-groups correspond poorly with diagnostic criteria for functional dyspepsia and irritable bowel syndrome. A factor and cluster analysis of a patient sample. Aliment Pharmacol Ther. 2004;19:133-140.

15. Aro P, Talley NJ, Ronkainen J, et al. Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study. Gastroenterology. 2009;137:94-100.

16. Mertz H, Fullerton S, Naliboff B, et al. Symptoms and visceral perception in severe functional and organic dyspepsia. Gut. 1998;42:814-822.

17. O’Morain C. Role of Helicobacter pylori in functional dyspepsia. World J Gastroenterol. 2006;12:2677-2680.

18. Shmuely H, Obure S, Passaro DJ, et al. Dyspepsia symptoms and Helicobacter pylori infection, Nakuru, Kenya. Emerg Infect Dis. 2003;9:1103-1107.

19. Barbara G, Zecchi L, Barbaro R, et al. Mucosal permeability and immune activation as potential therapeutic targets of probiotics in irritable bowel syndrome. J Clin Gastroenterol. 2012;46(suppl):S52-S55.

20. Liu NJ, Lee CS, Tang JH, et al. Outcomes of bleeding peptic ulcers: a prospective study. J Gastroenterol Hepatol. 2008;23:e340-e347.

21. Ramsoekh D, van Leerdam ME, Rauws EA, et al. Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori infection. Clin Gastroenterol Hepatol. 2005;3:859-864.

22. Papatheodoridis GV, Sougioultzis S, Archimandritis AJ. Effects of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on peptic ulcer disease: a systematic review. Clin Gastroenterol Hepatol. 2006;4:130-142.

23. Bai Y, Li ZS, Zou DW, et al. Alarm features and age for predicting upper gastrointestinal malignancy in Chinese patients with dyspepsia with high background prevalence of Helicobacter pylori infection and upper gastrointestinal malignancy: an endoscopic database review of 102,665 patients from 1996 to 2006. Gut. 2010;59:722-728.

24. Vakil N. Dyspepsia, peptic ulcer, and H. pylori: a remembrance of things past. Am J Gastroenterol. 2010;105:572-574.

25. Shaheen NJ, Weinberg DS, Denberg TD, et al; Clinical Guidelines Committee of the American College of Physicians. Upper endoscopy for gastroesophageal reflux disease: best practice advice from the clinical guidelines committee of the American College of Physicians. Ann Intern Med. 2012;157:808-816.

26. Moayyedi P, Soo S, Deeks J, et al. Pharmacological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006;(4):CD001960.

27. Chiu CT, Hsu CM, Wang CC, et al. Randomised clinical trial: sodium alginate oral suspension is non-inferior to omeprazole in the treatment of patients with non-erosive gastroesophageal disease. Aliment Pharmacol Ther. 2013;38:1054-1064.

28. Veldhuyzen van Zanten SJ, Chiba N, Armstrong D, et al. A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in helicobacter pylori negative, primary care patients with dyspepsia: the CADET-HN Study. Am J Gastroenterol. 2005;100:1477-1488.

29. Moayyedi P, Delaney BC, Vakil N, et al. The efficacy of proton pump inhibitors in nonulcer dyspepsia: a systematic review and economic analysis. Gastroenterology. 2004;127:1329-1337.

30. Garza-González E, Bosques-Padilla FJ, Tijerina-Menchaca R, et al. Comparison of endoscopy-based and serum-based methods for the diagnosis of Helicobacter pylori. Can J Gastroenterol. 2003;17:101-106.

31. Kodama M, Murakami K, Okimoto T, et al. Influence of proton pump inhibitor treatment on Helicobacter pylori stool antigen test. World J Gastroenterol. 2012;18:44-48.

32. Shimoyama T. Stool antigen tests for the management of Helicobacter pylori infection. World J Gastroenterol. 2013;19:8188-8191.

33. Howden CW, Hunt RH. Guidelines for the management of Helicobacter pylori infection. Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. Am J Gastroenterol. 1998;93:2330-2338.

34. Gisbert J, Abraira V. Accuracy of Helicobacter pylori diagnostic tests in patients with bleeding peptic ulcer: a systematic review and meta-analysis. Am J Gastroenterol. 2006;101:848-863.

35. Kamangar F, Dawsey SM, Blaser MJ, et al. Opposing risks of gastric cardiac and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst. 2006;98:1445-1452.

36. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis. Cancer Prevent Res (Phila). 2008;1:329-338.

37. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2006;(2):CD002096.

38. Mazzoleni LE, Sander GB, Francesconi CF, et al. Helicobacter pylori eradication in functional dyspepsia: HEROES trial. Arch Intern Med. 2011;171:1929-1936.

39. Yuan Y, Ford AC, Khan KJ, et al. Optimum duration of regimens for Helicobacter pylori eradication. Cochrane Database Syst Rev. 2013;(12):CD008337.

40. Zou J, Dong J, Yu X. Meta-analysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for Helicobacter pylori eradication. Helicobacter. 2009;14:97-107.

41. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple therapy for the eradication of Helicobacter pylori. Am J Gastroenterol. 2011;106:1970-1975.

42. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant therapy with 4 drugs are equally effective for eradication of H. pylori infection. Clin Gastroenterol Hepatol. 2010;8:36–41.

43. Osato R, Reddy R, Reddy SG, et al. Pattern of primary resistance of Helicobacter pylori to metronidazole or clarithromycin in the United States. Arch Intern Med. 2001;161:1217-1220.

44. Fischbach L, Evans EL. Meta-analysis: the effect of antibiotic resistance status on the efficacy of triple and quadruple firstline therapies for Helicobacter pylori. Aliment Pharmacol Ther. 2007;26:343-357.

45. Hinostroza Morales D, Díaz Ferrer J. Addition of bismuth subsalicylate to triple eradication therapy for Helicobacter pylori infection: efficiency and adverse events. Rev Gastroenterol Peru. 2014;34:315-320.

46. Rabeneck L, Wristers K, Souchek J, et al. Impact of upper endoscopy on satisfaction in patients with previously uninvestigated dyspepsia. Gastrointest Endosc. 2003;57:295-299.

47. Hojo M, Miwa H, Yokoyama T, et al. Treatment of functional dyspepsia with antianxiety or antidepressive agents: systematic review. J Gastroenterol. 2005;40:1036-1042.

48. Soo S, Moayyedi P, Deeks J, et al. Psychological interventions for non-ulcer dyspepsia. Cochrane Database Syst Rev. 2005;(2):CD002301.

49. Lima FA, Ferreira LE, Pace FH. Acupuncture effectiveness as a complementary therapy in functional dyspepsia patients. Arq Gastroenterol. 2013;50:202-207.

50. Ma TT, Yu SY, Li Y, et al. Randomised clinical trial: an assessment of acupuncture on specific meridian or specific acupoint vs. sham acupuncture for treating functional dyspepsia. Aliment Pharmacol Ther. 2012;35:552-561.

51. Koretz RL, Rotblatt M. Complementary and alternative medicine in gastroenterology: the good, the bad, and the ugly. Clin Gastroenterol Hepatol. 2004;2:957-967.

In a 2006 Cochrane Review, treating H pylori had a small but statistically significant benefit for patients with FD (NNT=14).³⁷ A 2011 study on the effects of H pylori eradication on symptoms and quality of life in primary care patients with FD revealed a 12.5% improvement in quality of life and a 10.6% improvement in symptoms.³⁸

The triple therapy regimen (a PPI + amoxicillin + clarithromycin) is the most common first-line H pylori treatment in the United States, and a good initial choice in regions in which clarithromycin resistance is low (TABLE 2).^39-44 The standard duration is 7 days. A 2013 Cochrane Review showed that a longer duration (14 days) increased the rate of eradication (82% vs 73%), but this remains controversial.³⁹ The addition of bismuth subsalicylate to the triple therapy regimen has been shown to increase the eradication rate of H pylori by approximately 10%.⁴⁵ Adding probiotics (saccharomyces or lactobacillus) appears to increase eradication rates, as well.⁴⁰

Sequential therapy consists of a 5-day course of treatment in which a PPI and amoxicillin are taken twice a day, followed by another 5-day course of a PPI, clarithromycin, and metronidazole. A recent meta-analysis of sequential therapy showed that it is superior to 7-day triple therapy but equivalent to 14-day triple therapy.⁴⁰

LOAD (levofloxacin, omeprazole, nitazoxanide, and doxycycline) therapy for 7 to 10 days can be used in place of triple therapy in areas of high resistance or for persistent H pylori. In one study, the H pylori eradication rate for a 7-day course of LOAD therapy—levofloxacin and doxycycline taken once a day, omeprazole before breakfast, and nitazoxanide twice daily—was 90% vs 73.3% for a 7-day course of triple therapy.⁴¹

Quadruple therapy has 2 variations: bismuth-based and non-bismuth (concomitant) therapy. The latter uses the base triple therapy and adds either metronidazole or tinidazole for 7 to 14 days. In a multicenter randomized trial, this concomitant therapy was found to have similar efficacy to sequential therapy.⁴²

The possibility of improving dyspepsia symptoms is a reason to treat H pylori infection, although eradicating it does not always do so.

Bismuth-based quad therapy includes a PPI, bismuth, metronidazole, and tetracycline. A meta-analysis found it to have a higher rate of eradication than triple therapy for patients with antibiotic resistance.^43,44

For persistent H pylori, a PPI, levofloxacin, and amoxicillin for 10 days has been shown to be more effective and better tolerated than quadruple therapy.¹²

Confirmation is indicated when symptoms persist

If dyspepsia symptoms persist after H pylori treatment, it is reasonable to retest to confirm that the infection has in fact been eradicated. Confirmation is also indicated if the patient has an H pylori-associated ulcer or a prior history of gastric cancer.

Retesting should be performed at least 4 to 6 weeks after treatment is completed. If H pylori has not been eradicated, you can try another regimen. If retesting confirms eradication and symptoms persist, EGD with biopsy is indicated. Although EGD typically has a very low yield, even for patients with red flags, this invasive test often provides reassurance and increased satisfaction for patients with persistent symptoms.⁴⁶

More options for challenging cases

Managing FD is challenging when both initial acid suppression therapy and H pylori eradication fail. Unproven but low-risk treatments include modification of eating habits (eg, eating slower, not gulping food), reducing stress, discontinuing medications that may be related to symptoms, avoiding foods that seem to exacerbate symptoms, and cutting down or eliminating tobacco, caffeine, alcohol, and carbonated beverages.⁸ Bismuth salts have been shown to be superior to placebo for the treatment of dyspepsia.²⁵ Small studies have also demonstrated a favorable risk–benefit ratio for peppermint oil and caraway oil for the treatment of FD.⁴⁷ Prokinetics have shown efficacy compared with placebo, although a Cochrane review questioned their efficacy based on publication bias.²⁶

There is no good evidence of efficacy for over-the-counter antacids, such as TUMS, or for GI “cocktails” (antacid, antispasmotic, and lidocaine), sucralfate, psychological interventions (eg, cognitive behavioral therapy, relaxation therapy, or hypnosis), or antidepressants.^48,49 Several recent randomized controlled trials have shown the efficacy of acupuncture for the treatment of dyspepsia.^49,50 Ginger may also be helpful; it has been found to help with nausea in other GI conditions, but it’s uncertain whether it can help patients with dyspepsia.⁵¹

CORRESPONDENCE
Michael Malone, MD, 845 Fishburn Road, Hershey, PA 17053; mmalone@hmc.psu.edu