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

Satapathy P 1 , Khatib MN 2 , Vadia N 3 , Menon SV 4 , Chennakesavulu K 5 , Panigrahi R 6 Show all authors , Shabil M 7 , Singh M 8 , Sah S 9 , Lingamaiah D 10 , Goh KW 11 , Mawejje E 12 , Bushi G 13

Affiliations 

  • 1 Center for Global Health Research, Saveetha Institute of Medical and Technical Sciences, Saveetha Medical College and Hospital, Saveetha University, Chennai, India. prakasini.satapathy@gmail.com
  • 2 Division of Evidence Synthesis, Global Consortium of Public Health and Research, Datta Meghe Institute of Higher Educatsion, Wardha, India. nazlikhatib@dmiher.edu.in
  • 3 Department of Pharmaceutical Sciences, Faculty of Health Sciences, Marwadi University Research Center, Marwadi University, Rajkot, Gujarat, 360003, India
  • 4 Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India
  • 5 Department of Chemistry, Sathyabama Institute of Science and Technology, Chennai, Tamil Nadu, India
  • 6 Department of Microbiology, IMS and SUM Hospital, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, Odisha, 751003, India
  • 7 University Center for Research and Development, Chandigarh University, Mohali, Punjab, India
  • 8 Department of Biotechnology, Graphic Era (Deemed to be University), Clement Town, Dehradun, 248002, India
  • 9 Department of Pediatrics, Hospital and Research Centre, Dr. D. Y. Patil Medical College, Dr. D. Y. Patil Vidyapeeth (Deemed-to-be-University), Pimpri, Pune, Maharashtra, 411018, India
  • 10 Chitkara Centre for Research and Development, Chitkara University Institute of Engineering and Technology, Chitkara University, Himachal Pradesh, 174103, India
  • 11 Faculty of Data Science and Information Technology, INTI International University, Nilai, Malaysia
  • 12 School of Public Health, Makerere University College of Health Sciences, Mulago Hill, Kampala, Uganda. emawejje62@gmail.com
  • 13 Centre Centre for Research Impact and Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, Punjab, 140401, India. ganeshbushi313@gmail.com
J Headache Pain, 2025 Mar 28;26(1):63.
PMID: 40155825 DOI: 10.1186/s10194-025-02000-8

Abstract

BACKGROUND: 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.

METHOD: 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.

RESULTS: 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.

CONCLUSION: 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.

CLINICAL TRIAL NUMBER: Not applicable.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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