Dyspepsia

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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 [1][2] 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. It may be called indigestion. Heartburn is excluded from the definition of dyspesia in ICD 10, as it usually has a different cause and management pathway. When a patient has dyspepsia, but underlying disease is found, the patient is said to have non-ulcer dyspepsia or functional dyspepsia or idopathic dyspepsia.

Classification

Dyspepsia has been proposed to have symptomatic subgroups:[3][4][5]

  • ulcerlike - "Pain centered in the upper abdomen is the predominant (most bothersome) symptom."[3]
  • dysmotilitylike - "An unpleasant or troublesome non-painful sensation (discomfort) centered in the upper abdomen is the predominant symptom; this sensation may be characterized by or associated with upper abdominal fullness, early satiety, bloating, or nausea."[3]
  • refluxlike
  • nonspecific

However, there is not a strong correlation of symptom type and measures of abnormal motility or hypersensitivity.[5][6]

A cluster analysis identified 4 groups, the first two are associated with delayed gastric emptying and the second two are associated with gastric hypersensitivity:[7]

  • Factor 1 - "characterized by nausea, vomiting, early satiety, and weight loss...associated with delayed emptying...younger age, female sex, and sickness behavior"
  • Factor 2 - "characterized by postprandial fullness and bloating...associated with delayed emptying"
  • Factor 3 - "characterized by pain symptoms and associated with gastric hypersensitivity and several psychosocial dimensions including medically unexplained symptoms and health-related quality of life dimensions".
  • Factor 4 - "characterized by belching, is also associated with hypersensitivity, but is unrelated to psychosocial dimensions."

Cause/etiology

Some cases are caused by medications such as calcium antagonists, nitrates, theophyllines, bisphosphonates, corticosteroids and non-steroidal anti-inflammatory drugs [NSAIDs]).[2]

Several studies provide prevalences of underlying causes based on findings at esophagogastroduodenoscopy (EGD).[8][5][9][10] [11]

Findings in various populations
Patients referred to gastroenterologists for dyspesia[5] Primary care patients with dyspepsia[9] Volunteers with dyspepsia[8] Volunteers without dyspepsia[8] Volunteers without dyspepsia[10] Referred patients in China[11]
Normal
Macroscopically normal
by EGD
60% 54% 73% 82% 66%
Histologically normal
by biopsy at EGD
35%
Esophagus
Macroscopic esophagitis
by EGD
14% 12% 13% 9% 22%
(included Grades
1 & 2)
Hiatal hernia >2 cm by UGI 40% 26%
Hiatal hernia by EGD 3% 3%
Stomach/duodenum
Peptic ulcer disease (PUD) 20% 8% 9% 4% 4%
Gastritis/duodenitis 14% 20% 5%
(erosions required)
5%
(erosions required)
9-16%
Other
Malignancy 3% 0% 0.4% 0.5% 0% 4%

Non-ulcer dyspepsia (NUD)

Rome criteria

Nonulcer dyspepsia exists (functional dyspepsia) when esophagogastroduodenoscopy and other tests have excluded other diseases and the patient has the following Rome II criteria:[3] At least 12 weeks, which need not be consecutive, within the preceding 12 months of:

  1. Persistent or recurrent dyspepsia (pain or discomfort centered in the upper abdomen); and
  2. No evidence of organic disease (including at upper endoscopy) that is likely to explain the symptoms; and
  3. No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or stool form (i.e., not irritable bowel).

Possible causes of NUD

The implied lack of organic disease may actually be incorrect as there may be physiological abnormalities that are too subtle for commonly used tests. For example, some patients may have gastric motor function or visceral sensitivity.[6][7]

Non-ulcer dyspepsia, when of acute onset, may be due to gastric dysmotor dysfunction following gastrointestinal infections.[12]

H. pylori

The role of H. pylori is not clear.

Association with other diseases

Psychiatric diagnoses

Psychiatric diagnoses are more prevalent among patients with normal endoscopies than abnormal endoscopies.[13]

Irritable bowel
For more information, see: Irritable bowel syndrome.

There is much overlap among patients with non-ulcer dyspepsia and irritable bowel syndrome.[14]

Celiac disease
For more information, see: Celiac disease.

Using historical controls, non-ulcer dyspepsia has been found to associate with celiac disease.[15]

Diagnosis

History and physical examination

The history and physical examination cannot reliably detect when organic disease underlies dypspepsia.[16]

Alarm features or red flags that may indicate serious underlying diseases are:[17]

  • Age older than 55 years with new-onset dyspepsia
  • Family history of upper gastrointestinal cancer
  • Unintended weight loss
  • Gastrointestinal bleeding
  • Progressive dysphagia
  • Odynophagia
  • Unexplained iron-deficiency anemia
  • Persistent vomiting
  • Palpable mass or lymphadenopathy
  • Jaundice

Although the value of these findings is hard to establish[18], one study found that the best predictions of abnormal investigations were:[19]

  • History of an previous ulcer
  • Age 50 or more
  • Pain better with food or milk (presumably identifies duodenal pathology)
  • Pain occurs < one hour after eating (presumably identifies gastric pathology)

Regarding gastric cancer, helpful findings are anemia and persistence of symptoms.[20]

Identifying a psychiatric disorder may reduce the chance than a serious organic disorder is present.[13]

On physical examination, pallor of conjunctiva, nail-bed or palmar crease, or the absence of nail-bed blanching are predictive of significant anemia (hemoglobin less than 12 gm/dl).[21]

Laboratory tests

Complete blood count

One study found that by using "H. pylori serology and a hemoglobin reading in the evaluation of dyspeptic patients under 45 years of age, the need for endoscopy can be reduced by 55%."[22]

In adults, 60% of patients with iron deficiency anemia may have underlying gastrointestinal disorders leading to chronic blood loss.[23]

H. pylori testing

Clinical practice guidelines by the American Gastroenterological Association state "H. pylori testing is optimally performed by a 13C-urea breath test or stool antigen test."[24]

Several studies indicate the need to test dyspeptic patients for H. pylori.[22][25][26][27] One study found that by using "H. pylori serology and a hemoglobin reading in the evaluation of dyspeptic patients under 45 years of age, the need for endoscopy can be reduced by 55%."[22]

A randomized controlled trial found that among patients without alarm symptoms, the cost of breath testing all patients is offset by the reduction in endoscopy.[28]

The accuracy of the breath test for detecting peptic ulcer disease is:[29]

False negative tests

Testing should be delayed for 2 weeks after stopping PPI use to avoid false negative breath test or a stool antigen test.[2]

Impact of testing

In summary, test and treat may reduce symptoms at two months with no improvement at one year.

"While early endoscopy offered some advantages 'Test and treat' was the most cost-effective strategy" according to a randomized controlled trial. [30] In this trial, the relative benefit ratio of Helicobacter pylori serum testing for improvement at 2 months was 1.2 and, the relative benefit increase was 23.7%. In populations similar to those in this study which had a rate of benefit as measured by the improvement at 2 months of 59% without treatment, the number needed to treat is 7. [30] There were no differences at 12 months.

"Test and treat and acid suppression are equally cost effective in the initial management of dyspepsia" according to a randomized controlled trial. [28] In this trial, the relative benefit ratio of Helicobacter pylori breath testing for no dyspepsia at one year was 1.1 and, the relative benefit increase was 5.9%. In populations similar to those in this study which had a rate of benefit as measured by the no dyspepsia at one year of 17% without treatment, the number needed to treat is 100. [28]

Other tests

Blood tests for celiac disease.[15]

Radiology

UGI as historic significance as good before EGD.[31]

Esophagogastroduodenoscopy (EGD)

Direct visualization by esophagogastroduodenoscopy(EGD) is very sensitive for peptic ulcer disease, but may not detect all possible underlying causes of dyspepsia. For example, gastroesophageal reflux disease that does not cause macroscopic esophagitis will be missed by esophagogastroduodenoscopy.[32]

For patients with positive Helicobacter pylori tests, obtaining endoscopy may be reasonable alternative to empiric antibiotics though less well studied.[33][30] This strategy allows identification of patients with GERD and also may reduce discontinuing antibiotics due to adverse drug reactions.[34]

For patients with negative Helicobacter pylori testing, endoscopy is not needed if they are less than 45 years old and without alarm symptoms.[35]

Diagnostic strategy

Many randomized controlled trials have compared empiric treatment (either for Helicobacter pylori or acid suppression), routine Helicobacter pylori testing, and routine esophagogastroduodenoscopy (EGD). These are summarized in a meta-analysis by the Cochrane Collaboration.[33] Additional trials have been published since the review by the Cochrane.[30][28][22][25][26][27]

Treatment

Clinical practice guidelines by the American Gastroenterological Association address treatment.[24]

The type of dyspepsia, motility versus acid, may weakly predict which medicine will reduce symptoms.[36][4]

Reassurance

Regarding the treatment of non-ulcer dyspepsia, the value of simple reassurance is suggested by the response to placebo ranging from 40%[37] to 70%.[38]

Smaller meals

Acid suppression

A meta-analysis of randomized controlled trials by the Cochrane Collaboration concluded "there is evidence that anti-secretory therapy may be effective in NUD" with a number needed to treat for PPIs of 10.[39] Subsequent randomized controlled trials have had conflicting results reporting both benefit[40] and no benefit.[38] Stepping up therapy may be better than stepping down therapy.[41]

As needed use of histamine H2 antagonists may be effective.[42]

Prokinetic drugs

Prokinetic drugs include:[43]

The Cochrane Collaboration concluded "trials evaluating prokinetic therapy are difficult to interpret as the...[positive] result could have been due to publication bias.".[39] More recently, a randomized controlled trial of itopride found that 100 mg three times per day benefited 17% of patients (number needed to treat is 6).[37]

Tricylic antidepressants

A meta-analysis found that patients needed to be treated to improve 1 patient (number needed to treat is 3).[44]

Eradication of H. pylori

In order to treat underlying peptic ulcer, clinical practice guidelines by the American Gastroenterological Association recommend:[24]

  • "Patients 55 years of age or younger without alarm features should receive Helicobacter pylori test and treat followed by acid suppression if symptoms remain"

The Cochrane Collaboration concluded "small but statistically significant effect in H. pylori positive non-ulcer dyspepsia. The number needed to treat was 14. An economic model suggests this modest benefit may still be cost-effective but more research is needed."[45] A more recent randomized controlled trial did not find a difference.[28]

The effect of eradication seems related to the presence of gastritis. Patients with antral predominant gastritis are more likely to improve whereas patients with corpus-predominant gastritis are less likely to improve.[46] This may be due to antral erosions being due to hyperacidity the is corrected by treatment whereas corpus erosions are hypoacidic and treating this may increase the ability of the stomach to produce acid. [46] Another study found that patients with gastritis or erosions were less likely to respond[47], but this study did not separate patients with antral versus corpus erosions.

Psychological interventions

It is unclear if any form of psychological interventions is beneficial[48]

Prevention

Users of nonsteroidal anti-inflammatory (NSAID) medications

Patients with a history of bleeding ulcer have a 26% rate of ulcers with NSAIDs.[49] Patients with H. pylori have 2.5 risk of an ulcer on NSAIDs.[50]

For patients starting long-term NSAIDs, screening for H. pylori with a breath test among patients with prior ulcer or dyspepsia and treating positive patients reduced subsequent rate of ulcers.[51] [52]

For patients who must take NSAIDs, proton pump inhibitors may be effective in preventing dyspepsia.[53]

Asymptomatic adults

Community screening for H. pylori may be beneficial.[54]

References

  1. Talley NJ, Vakil N (2005). "Guidelines for the management of dyspepsia". Am. J. Gastroenterol. 100 (10): 2324–37. DOI:10.1111/j.1572-0241.2005.00225.x. PMID 16181387. Research Blogging.
  2. 2.0 2.1 2.2 National Institute for Health and Clinical Excellence. 2004. Dyspepsia. August, 2004. http://guidance.nice.org.uk/CG17 (accessed October 12, 2007)
  3. 3.0 3.1 3.2 3.3 Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada JR, Tytgat GN (1999). "Functional gastroduodenal disorders". Gut 45 Suppl 2: II37–42. PMID 10457043[e]
  4. 4.0 4.1 Talley NJ, Phung N, Kalantar JS (2001). "ABC of the upper gastrointestingal tract: Indigestion: When is it functional?". BMJ 323 (7324): 1294–7. PMID 11731396[e]
  5. 5.0 5.1 5.2 5.3 Talley NJ, Weaver AL, Tesmer DL, Zinsmeister AR (1993). "Lack of discriminant value of dyspepsia subgroups in patients referred for upper endoscopy". Gastroenterology 105 (5): 1378–86. DOI:0.1136/bmj.323.7324.1294. PMID 8224642. Research Blogging.
  6. 6.0 6.1 Karamanolis G, Caenepeel P, Arts J, Tack J (2006). "Association of the predominant symptom with clinical characteristics and pathophysiological mechanisms in functional dyspepsia". Gastroenterology 130 (2): 296–303. DOI:10.1053/j.gastro.2005.10.019. PMID 16472585. Research Blogging.
  7. 7.0 7.1 Fischler B, Tack J, De Gucht V, et al (2003). "Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia". Gastroenterology 124 (4): 903–10. DOI:10.1053/gast.2003.50155. PMID 12671886. Research Blogging.
  8. 8.0 8.1 8.2 Zagari RM, Law GR, Fuccio L, Pozzato P, Forman D, Bazzoli F (2010). "Dyspeptic symptoms and endoscopic findings in the community: the Loiano-Monghidoro study.". Am J Gastroenterol 105 (3): 565-71. DOI:10.1038/ajg.2009.706. PMID 20010920. Research Blogging.
  9. 9.0 9.1 Williams B, Luckas M, Ellingham JH, Dain A, Wicks AC (1988). "Do young patients with dyspepsia need investigation?". Lancet 2 (8624): 1349–51. PMID 2904061[e]
  10. 10.0 10.1 Johnsen R, Bernersen B, Straume B, Førde OH, Bostad L, Burhol PG (1991). "Prevalences of endoscopic and histological findings in subjects with and without dyspepsia". BMJ 302 (6779): 749–52. PMID 2021764[e] Fulltext
  11. 11.0 11.1 Bai Y, Li ZS, Zou DW, Wu RP, Yao YZ, Jin ZD et al. (2010). "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 59 (6): 722-8. DOI:10.1136/gut.2009.192401. PMID 20551455. Research Blogging.
  12. Tack J, Demedts I, Dehondt G, et al (2002). "Clinical and pathophysiological characteristics of acute-onset functional dyspepsia". Gastroenterology 122 (7): 1738–47. PMID 12055579[e]
  13. 13.0 13.1 O'Malley PG, Wong PW, Kroenke K, Roy MJ, Wong RK (1998). "The value of screening for psychiatric disorders prior to upper endoscopy". Journal of psychosomatic research 44 (2): 279–87. PMID 9532557[e]
  14. Agréus L, Svärdsudd K, Nyrén O, Tibblin G (1995). "Irritable bowel syndrome and dyspepsia in the general population: overlap and lack of stability over time". Gastroenterology 109 (3): 671–80. PMID 7657095[e]
  15. 15.0 15.1 Ozaslan E, Akkorlu S, Eskioğlu E, Kayhan B (2007). "Prevalence of silent celiac disease in patients with dyspepsia". Dig. Dis. Sci. 52 (3): 692–7. DOI:10.1007/s10620-006-9453-1. PMID 17235704. Research Blogging.
  16. Moayyedi P, Talley NJ, Fennerty MB, Vakil N (2006). "Can the clinical history distinguish between organic and functional dyspepsia?". JAMA 295 (13): 1566–76. DOI:10.1001/jama.295.13.1566. PMID 16595759. Research Blogging.
  17. Talley NJ, Vakil NB, Moayyedi P (2005). "American gastroenterological association technical review on the evaluation of dyspepsia". Gastroenterology 129 (5): 1756–80. DOI:10.1053/j.gastro.2005.09.020. PMID 16285971. Research Blogging.
  18. Hammer J, Eslick GD, Howell SC, Altiparmak E, Talley NJ (2004). "Diagnostic yield of alarm features in irritable bowel syndrome and functional dyspepsia". Gut 53 (5): 666–72. PMID 15082584[e]
  19. Marton KI, Sox HC, Wasson J, Duisenberg CE (1980). "The clinical value of the upper gastrointestinal tract roentgenogram series". Arch. Intern. Med. 140 (2): 191–5. PMID 7352814[e]
  20. Gillen D, McColl KE (1999). "Does concern about missing malignancy justify endoscopy in uncomplicated dyspepsia in patients aged less than 55?". Am. J. Gastroenterol. 94 (1): 75–9. PMID 9934734[e]
  21. Nardone DA, Roth KM, Mazur DJ, McAfee JH (1990). "Usefulness of physical examination in detecting the presence or absence of anemia". Arch. Intern. Med. 150 (1): 201–4. PMID 2297289[e]
  22. 22.0 22.1 22.2 22.3 Valle PC, Breckan RK, Amin A, et al (2006). ""Test, score and scope": a selection strategy for safe reduction of upper gastrointestinal endoscopies in young dyspeptic patients referred from primary care". Scand. J. Gastroenterol. 41 (2): 161–9. DOI:10.1080/00365520500286881. PMID 16484121. Research Blogging.
  23. Rockey D, Cello J (1993). "Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia". N Engl J Med 329 (23): 1691-5. PMID 8179652.
  24. 24.0 24.1 24.2 Talley NJ (2005). "American Gastroenterological Association medical position statement: evaluation of dyspepsia". Gastroenterology 129 (5): 1753–5. DOI:10.1053/j.gastro.2005.09.019. PMID 16285970. Research Blogging. National Guideline Clearinghouse
  25. 25.0 25.1 Jarbol DE, Kragstrup J, Stovring H, Havelund T, Schaffalitzky de Muckadell OB (2006). "Proton pump inhibitor or testing for Helicobacter pylori as the first step for patients presenting with dyspepsia? A cluster-randomized trial". Am. J. Gastroenterol. 101 (6): 1200–8. DOI:10.1111/j.1572-0241.2006.00673.x. PMID 16771937. Research Blogging.
  26. 26.0 26.1 Arents NL, Thijs JC, van Zwet AA, et al (2003). "Approach to treatment of dyspepsia in primary care: a randomized trial comparing "test-and-treat" with prompt endoscopy". Arch. Intern. Med. 163 (13): 1606–12. DOI:10.1001/archinte.163.13.1606. PMID 12860586. Research Blogging.
  27. 27.0 27.1 Shaw IS, Valori RM, Charlett A, McNulty CA (2006). "Limited impact on endoscopy demand from a primary care based 'test and treat' dyspepsia management strategy: the results of a randomised controlled trial". The British journal of general practice : the journal of the Royal College of General Practitioners 56 (526): 369–74. PMID 16638253[e]
  28. 28.0 28.1 28.2 28.3 28.4 Delaney BC, Qume M, Moayyedi P, et al (March 2008). "Helicobacter pylori test and treat versus proton pump inhibitor in initial management of dyspepsia in primary care: multicentre randomised controlled trial (MRC-CUBE trial)". BMJ 336 (7645): 651–4. DOI:10.1136/bmj.39479.640486.AE. PMID 18310262. Research Blogging.
  29. McColl KE, el-Nujumi A, Murray L, et al (1997). "The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients". Gut 40 (3): 302–6. PMID 9135516[e]
  30. 30.0 30.1 30.2 30.3 Duggan AE, Elliott CA, Miller P, Hawkey CJ, Logan RF (2009). "Clinical trial: a randomized trial of early endoscopy, Helicobacter pylori testing and empirical therapy for the management of dyspepsia in primary care.". Aliment Pharmacol Ther 29 (1): 55-68. DOI:10.1111/j.1365-2036.2008.03852.x. PMID 18801056. Research Blogging.
  31. (1985) "Endoscopy in the evaluation of dyspepsia. Health and Public Policy Committee, American College of Physicians". Ann. Intern. Med. 102 (2): 266–9. PMID 3917639[e]
  32. Tefera L, Fein M, Ritter MP, et al (1997). "Can the combination of symptoms and endoscopy confirm the presence of gastroesophageal reflux disease?". The American surgeon 63 (10): 933–6. PMID 9322676[e]
  33. 33.0 33.1 Delaney B, Ford AC, Forman D, Moayyedi P, Qume M (2005). "Initial management strategies for dyspepsia". Cochrane database of systematic reviews (Online) (4): CD001961. DOI:10.1002/14651858.CD001961.pub2. PMID 16235292. Research Blogging.
  34. Heaney A, Collins JS, Watson RG, McFarland RJ, Bamford KB, Tham TC (1999). "A prospective randomised trial of a "test and treat" policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic". Gut 45 (2): 186–90. PMID 10403729[e]
  35. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC (1998). "A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia". European journal of gastroenterology & hepatology 10 (12): 983–9. PMID 9895042[e]
  36. Hansen JM, Bytzer P, Schaffalitzky De Muckadell OB (1998). "Management of dyspeptic patients in primary care. Value of the unaided clinical diagnosis and of dyspepsia subgrouping". Scand. J. Gastroenterol. 33 (8): 799–805. PMID 9754725[e]
  37. 37.0 37.1 Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C (2006). "A placebo-controlled trial of itopride in functional dyspepsia". N. Engl. J. Med. 354 (8): 832–40. DOI:10.1056/NEJMoa052639. PMID 16495395. Research Blogging.
  38. 38.0 38.1 Leung WK, Wu JC, Chan FK, et al (2007). "Initial treatment with lansoprazole in young dyspeptic patients with negative urea breath test result: a randomized controlled trial with 12-month follow-up". Am. J. Gastroenterol. 102 (7): 1483–8. DOI:10.1111/j.1572-0241.2007.01229.x. PMID 17593161. Research Blogging.
  39. 39.0 39.1 Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D (2006). "Pharmacological interventions for non-ulcer dyspepsia". Cochrane database of systematic reviews (Online) (4): CD001960. DOI:10.1002/14651858.CD001960.pub3. PMID 17054151. Research Blogging.
  40. van Zanten SV, Armstrong D, Chiba N, et al (2006). "Esomeprazole 40 mg once a day in patients with functional dyspepsia: the randomized, placebo-controlled "ENTER" trial". Am. J. Gastroenterol. 101 (9): 2096–106. DOI:10.1111/j.1572-0241.2006.00751.x. PMID 16817845. Research Blogging.
  41. Effect and cost-effectiveness of step-up versus step-down treatment with antacids, H2-receptor antagonists, and proton pump inhibitors in patients with new onset dyspepsia (DIAMOND study): a primary-care-based randomised controlled trial. Lancet. DOI:10.1016/S0140-6736(09)60070-2
  42. Johannessen T, Petersen H, Kristensen P, Fosstvedt D, Kleveland PM, Dybdahl J et al. (1992). "Cimetidine on-demand in dyspepsia. Experience with randomized controlled single-subject trials.". Scand J Gastroenterol 27 (3): 189-95. PMID 1502480.
  43. Hiyama T, Yoshihara M, Matsuo K, et al (2007). "Treatment of functional dyspepsia with serotonin agonists: A meta-analysis of randomized controlled trials". J. Gastroenterol. Hepatol. 22 (10): 1566–70. DOI:10.1111/j.1440-1746.2006.04723.x. PMID 17845684. Research Blogging.
  44. Jackson JL, O'Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K (2000). "Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis". Am. J. Med. 108 (1): 65–72. PMID 11059442[e]
  45. Moayyedi P, Soo S, Deeks J, et al (2006). "Eradication of Helicobacter pylori for non-ulcer dyspepsia". Cochrane database of systematic reviews (Online) (2): CD002096. DOI:10.1002/14651858.CD002096.pub4. PMID 16625554. Research Blogging.
  46. 46.0 46.1 Vakil N, Talley NJ, Stolte M, Sundin M, Junghard O, Bolling-Sternevald E (2006). "Patterns of gastritis and the effect of eradicating Helicobacter pylori on gastro-oesophageal reflux disease in Western patients with non-ulcer dyspepsia". Aliment. Pharmacol. Ther. 24 (1): 55–63. DOI:10.1111/j.1365-2036.2006.02964.x. PMID 16803603. Research Blogging.
  47. Mazzoleni LE, Sander GB, Ott EA, et al (2006). "Clinical outcomes of eradication of Helicobacter pylori in nonulcer dyspepsia in a population with a high prevalence of infection: results of a 12-month randomized, double blind, placebo-controlled study". Dig. Dis. Sci. 51 (1): 89–98. DOI:10.1007/s10620-006-3090-6. PMID 16416218. Research Blogging.
  48. Soo S, Moayyedi P, Deeks J, Delaney B, Lewis M, Forman D (2004). "Psychological interventions for non-ulcer dyspepsia". Cochrane database of systematic reviews (Online) (1): CD002301. DOI:10.1002/14651858.CD002301.pub2. PMID 14973988. Research Blogging.
  49. Spiegel BM, Targownik L, Dulai GS, Gralnek IM (2003). "The cost-effectiveness of cyclooxygenase-2 selective inhibitors in the management of chronic arthritis". Ann. Intern. Med. 138 (10): 795–806. PMID 12755551[e]
  50. Huang JQ, Sridhar S, Hunt RH (2002). "Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis". Lancet 359 (9300): 14–22. PMID 11809181[e]
  51. Chan FK, To KF, Wu JC, et al (2002). "Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial". Lancet 359 (9300): 9–13. PMID 11809180[e]
  52. Chan FK, Sung JJ, Chung SC, et al (1997). "Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers". Lancet 350 (9083): 975–9. PMID 9329511[e]
  53. Spiegel BM, Farid M, Dulai GS, Gralnek IM, Kanwal F (2006). "Comparing rates of dyspepsia with Coxibs vs NSAID+PPI: a meta-analysis". Am. J. Med. 119 (5): 448.e27–36. DOI:10.1016/j.amjmed.2005.11.020. PMID 16651060. Research Blogging.
  54. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P (2005). "A community screening program for Helicobacter pylori saves money: 10-year follow-up of a randomized controlled trial". Gastroenterology 129 (6): 1910–7. DOI:10.1053/j.gastro.2005.09.016. PMID 16344059. Research Blogging.