Association between proton pump inhibitor use and migraine: a systematic review and meta-analysis

Migraine is a common neurological disorder with potential pharmacological triggers. Proton pump inhibitors (PPIs), commonly prescribed for managing gastroesophageal reflux disease and other acid-related gastrointestinal disorders, have been linked to headaches. However, their association with migraine remains unclear. This systematic review and meta-analysis assessed the association between PPI use and the incidence of migraine.

A systematic search of PubMed, Embase, and Web of Science was conducted in accordance with the PRISMA framework and registered with PROSPERO (ID: CRD42025644604) to enhance transparency. The search, conducted up to January 2024, included studies focusing on the association between migraine and PPI use. Data screening and extraction were performed using Nested Knowledge software. Meta-analyses were conducted in R software, with heterogeneity assessed through the I² statistic. Pooled adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Sensitivity analyses were also performed to assess the robustness of the results. Gender and migraine subtype were considered in subgroup analyses. Additionally, the GRADE approach was applied to assess the certainty of the evidence across the pooled outcomes.

Five studies involving over 1.5 million participants met the inclusion criteria. The overall pooled adjusted odds ratio (aOR) was 2.508 (95% CI, 0.790-7.969; I² = 91.2%). However, there was a significant association in males (aOR, 3.875; 95% CI, 2.413-6.222; I² = 0%) but not in females (aOR, 2.475; 95% CI, 0.563-10.890; I² = 91.1%). No significant differences were found between migraine types: with aura (aOR, 2.079; 95% CI, 0.945-4.576; I² = 25.4%) and without aura (aOR, 2.524; 95% CI, 0.807-7.896; I² = 96.5%). The GRADE assessment indicated a very low certainty of the evidence.

This review found no significant overall association between PPI use and migraine. However, a significant association was observed in males but not in females. Further research is needed to clarify this association and explore the underlying causality mechanisms, and migraine subtypes, particularly why the association appears more pronounced in males.

Not applicable.