1. Non-ulcer dyspepsia (NUD) is definitively diagnosed by negative endoscopic findings despite the presence of upper GI symptoms. Just over half of all patients complaining of dyspepsia are ultimately diagnosed with NUD.

2. Endoscopy isn’t risk-free, and younger patients probably shouldn’t be referred unless symptoms defy treatment, or they have cancer alarm symptoms like weight loss, dysphagia, anemia, and black or bloody stool. In patients over age 50, early endoscopy may be worthwhile if uncomplicated dyspepsia is of new onset.

3. In the absence of alarm symptoms, a good first step is to test for H. pylori infection. About 7% of NUD patients are cured by H. pylori eradication. This is typically done with triple therapy of amoxicillin or metronidazole, plus clarithromycin and a proton pump inhibitor (PPI).

4. H. pylori eradication success rates have fallen recently, and hover around 80% depending on local strains. Some experts now suggest a 14-day regimen in place of the usual seven. In Canada, slightly better rates have been achieved with quadruple therapy of a PPI, bismuth, metronidazole and tetracycline for 7-10 days.

5. If symptoms persist after H. pylori eradication, test again. But this time, use the Carbon-14 breath test. Serological testing can show positive for two years even after successful eradication. If 14C test is positive, try second-line antibiotics.

6. Left untreated, about one in three cases of NUD will resolve naturally. In the rest, acid suppression is the goal. Three drug classes are used: antacids, H₂ antagonists, and PPIs.

7. In randomized controlled trials, antacids have done no better than placebo in treating NUD. But then, placebo itself can be surprisingly effective. NUD patients are more prone to anxiety, depression, and hypochondriasis than control subjects.

8. PPIs are extremely useful in treating peptic ulcers and GERD. But they may be overkill in NUD. Few patients need acid suppressed so completely. Use of PPIs has been associated with vitamin B₁₂ deficiency, and with sharply increased risk of C. difficile infection. PPIs also require about 24 hours to effectively suppress acid. Finally, they can lead to acid overproduction if stopped suddenly, so taper the dose over 2 weeks.

9. In most patients, H₂ blockers are just as effective as PPIs in controlling NUD symptoms, and can work faster. Promotility (prokinetic) drugs like domperidone may also help. If PPIs are the choice, consider a half-dose.

10. Down the pipeline? Potassium-competitive acid blockers and CCK₂-receptor antagonists are already in clinical trials, and behind them are an antigastrin vaccine, H₃-receptor ligands and gastrin-releasing peptide receptor antagonists. There are new long-acting PPIs coming too.