medRxiv ·10 Nov 2026 ·Added 10 Nov 2026

Gabapentinoid to Loop Diuretic Prescribing Cascade: A Systematic Review and Meta-Analysis of Observational Studies

A. Alami, L. de la Mora Vargas, I. Prada Betancourt, L. Lopez-Paternostro, E. A. Flores Boggiano, J. V. M. S. Martelli, L. Scabeni Pan, P. Vivanco-Aravena, O. Munoz-Narvaez, D. Montanini, M. Borba Osorio, S. Baroom, R. Cruz-Vicioso, Y. Ramirez, D. Abele, M. Santos-Salce, C. Collado, I. Resende da Gloria, F. Ramos, T. De Miranda, L. Mora-Marquez, A. Haseeb, F. Rossetto, G. Franceschini Machado

Preprint
Open access
Other & Emerging Fields

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Abstract

Introduction. Gabapentinoid-induced peripheral edema may be misinterpreted as a new condition and treated with a loop diuretic, creating a prescribing cascade. Objective. To synthesize evidence on the gabapentinoid-to-loop diuretic prescribing cascade in adults: its magnitude, dose- and drug-related gradients, timing, and downstream harms. Methods. We searched MEDLINE, Embase, PubMed, and Web of Science to 23 April 2026 (PROSPERO CRD420261379968) for studies of loop diuretic initiation after gabapentinoid initiation and assessed risk of bias with ROBINS-I. Findings were synthesized by study design, and adjusted sequence ratios were pooled in a random-effects meta-analysis. Results. Nine studies from five countries (>1.8 million new gabapentinoid users) were included: five sequence symmetry analyses, three cohort studies, and one chart review; six were restricted to older adults and two were available only as conference reports. All five sequence symmetry analyses and both cohort studies with an unexposed comparison group found more diuretic prescribing after gabapentinoid initiation. Sequence ratios ranged from 1.23 to 1.69, with a pooled adjusted sequence ratio of 1.37 (95% CI 1.14-1.64; I2= 96%; five estimates from four studies). Both of these cohort studies reported an adjusted hazard ratio of 1.44 (loop diuretics in one, any diuretic in the other). Higher doses were associated with larger estimates in four of the five studies that examined dose. In one chart review, 23.3% of patients had a potential harm within 60 days of starting a loop diuretic. Conclusions. Gabapentinoid initiation was associated with subsequent loop diuretic prescribing, mainly in older adults, consistent with a prescribing cascade. Clinicians may consider a recently started gabapentinoid as a possible cause of new edema before adding a loop diuretic.