Drug-induced symptoms of functional or acid-related dyspepsia. a sequence symmetry analysis of 1.5 million prescriptions

Background: Most patients with dyspeptic symptoms are treated empirically with ulcer drugs or prokinetics. Drug-induced dyspepsia might therefore be reflected in the sequencing of these drugs relative to other medications. Our aim was to screen a large prescription database for signs of drug-induced dyspepsia. Methods: Prescription data on all incident users of prokinetics (cisapride and metoclopramide) or ulcer drugs (H₂RA, PPI) were drawn from a large population-based research database. We identified all individuals, who had started their first recorded therapies with a prokinetic/ulcer drug and an index drug within a 100 day span, hi this selected group a dyspepsia-provoking effect of the index drug would manifest as an excess of persons with the prokinetic/ulcer drug prescribed last. This symmetry principle is robust to all confounders that are stable over time. We applied the method to a preselected list of 33 index drug classes. Results are presented as adjusted rate ratios (RR) with 95% CI. Results: In the cisapride analysis (1.825 persons) not a single drug or drug class had RRs significantly >1. hi the metoclopramide analysis (6.126 persons) positive signals was found for 12 drugs, all well-known for their nauseating sideeffects - except for ACEIs (RR 2.3, 1.5-3.9), loop-diuretics (RR 1.5, 1.2-1.9), corticosteroids (RR 1.3, 1.1-1.6) and NSAIDs (RR 1.5, 1.3-1.7). In the ulcer drug analysis (31.232 persons) significant RRs were found for NSAIDs (RR 1.8, 1.6-2.0), calcium blockers (RR 1.4, 1.2-1.7), and methylxanthines (RR 1.5, 1.12.2). Conclusions: Drug-induced symptoms of functional dyspepsia are very rare. There are no important unknown dyspepsinogenic drugs inducing acid-like dyspepsia. ACEIs, NSAIDs, loop-diuretics, and corticosteroids may possibly induce nausea. Prescription sequence symmetry analysis may be a reliable and powerful tool to identify drug related side effects.