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This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed\/MEDLINE, EMBASE, Cochrane CENTRAL via the Cochrane Library, Scopus, Web of Science Core Collection, and Google Scholar were searched from inception to 1 May 2026 without language restrictions. Randomized controlled trials and controlled observational studies in adults with glaucoma or ocular hypertension were eligible when topical pilocarpine, used alone or in combination, was compared with placebo, no treatment, laser trabeculoplasty, or other intraocular pressure (IOP)-lowering therapies. The primary outcome was mean change in IOP, and secondary outcomes included responder outcomes, ocular adverse events, discontinuation, visual field outcomes, medication burden, post-laser pressure spikes, and postoperative outcomes. Risk of bias was assessed with the Cochrane Risk of Bias 2.0 tool (RoB 2.0) for randomized studies and the Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tool for nonrandomized studies. We performed random-effects meta-analysis using raw mean difference in mmHg for continuous outcomes and risk ratio (RR) for binary safety outcomes, each reported with a 95% confidence interval (CI); certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Of the 38 studies that met the inclusion criteria, 34 contributed data to the quantitative meta-analysis. In the primary analysis, pilocarpine-containing regimens reduced IOP by an additional 1.16\u00a0mmHg compared to all comparators (95% CI 0.84 to 1.47;\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001;\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    \u2009=\u200950.7%). Subgroup analyses suggested larger pooled effects in placebo\/no-treatment comparisons, ocular hypertension, primary open-angle glaucoma, and monotherapy studies; however, comparisons with beta-blockers and prostaglandin analogs require cautious interpretation because several large individual trials favored timolol or latanoprost for daily clinical use, tolerability, or dosing convenience. Pilocarpine was associated with a sevenfold higher risk of blurred vision (RR 7.33; 95% CI 3.30 to 16.29) and a sixfold higher risk of discontinuation due to adverse events (RR 6.07; 95% CI 3.69 to 10.00). Egger\u2019s test pointed to funnel plot asymmetry (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.003), although the trim and fill method did not impute any missing studies. Pilocarpine lowers IOP effectively, but its modern role is limited by frequent dosing, miosis, blurred vision, accommodative symptoms, brow ache, and higher discontinuation. In current glaucoma care, prostaglandin analogs and selective laser trabeculoplasty are generally more consistent with first-line open-angle glaucoma management, whereas pilocarpine is better positioned for selected clinical scenarios, including angle-closure mechanisms, post-laser pressure-spike prophylaxis, selected postoperative angle-surgery settings, intolerance or nonresponse to other drug classes, and resource-limited settings where newer therapies are unavailable or unaffordable.\n                  <\/jats:p>","DOI":"10.1007\/s00210-026-05571-8","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:14:18Z","timestamp":1786421658000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Can pilocarpine effectively and safely manage glaucoma in the modern era? 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Therefore, no Institutional Review Board (IRB) or Ethics Committee approval was required, and the human ethics and consent to participate declarations are not applicable. All procedures were conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable. This article does not contain any individual person\u2019s data in any form.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":4,"name":"Ethics","label":"Clinical trial number","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors confirm that no artificial intelligence was used in the generation or submission of this manuscript.","order":5,"name":"Ethics","label":"Declaration on integrity and transparency","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"C.-M. C. (Chi-Ming Chan) is the guarantor of this work and accepts full responsibility for the integrity of the study, the accuracy of the data analysis, and the decision to submit the manuscript for publication. 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