Comments on efficacy and safety of pilocarpine hydrochloride ophthalmic solution USP 1.25% w/v versus placebo ophthalmic solution for the treatment of presbyopia – A multicentric clinical trial

Dear Editor, The study by Singh et al.[1] on pilocarpine hydrochloride 1.25% for presbyopia indicates a significant progression in the investigation of pharmacological approaches for near-vision correction. The GEMINI studies have shown encouraging short-term enhancements in near vision alongside an acceptable safety profile; nonetheless, certain methodological and interpretive concerns need consideration. The randomized, double-blind, vehicle-controlled Phase 3 GEMINI studies provide a significant advantage, yielding substantial data from over 750 patients. The study revealed statistically substantial enhancements in mesopic, high-contrast, binocular distance-corrected near visual acuity (DCNVA), with 30.7% of patients attaining a ≥3-line improvement by day 30, in contrast to 8.1% in the vehicle cohort (P < 0.0001). Significantly, adverse effects were predominantly mild to severe, with headache and conjunctival hyperemia being the most prevalent.[2] First, the limited 30-day follow-up period constrains the inferences that may be drawn about long-term safety and enduring effectiveness. Presbyopia is a lifelong condition, and under the current research parameters, treatment compliance, tachyphylaxis, or cumulative adverse effects (including chronic miosis, anterior chamber angle impairment, or progressive lens opacity, retinal detachment) cannot be discounted.[3,4] Second, the exclusion of individuals with prevalent ocular comorbidities (cataract, glaucoma, retinal disease) limits generalizability. In clinical practice, several presbyopic individuals exhibit concurrent ocular diseases. Consequently, the external validity of these results is ambiguous, and the drug’s safety profile in these groups has not been investigated. The mechanism of action—enhancement of depth of focus generated by miosis—elicits functional concerns. Although statistically substantial enhancements in DCNVA were attained, the effect on visual quality under mesopic and scotopic circumstances was insufficiently examined. Pilocarpine-induced miosis may impair nocturnal vision, diminish contrast sensitivity, and heighten glare—issues particularly relevant to patients’ everyday activities, such as nighttime driving.[2,5] The lack of comprehensive patient-reported outcome measures (PROs) is a notable deficiency in the research design. Finally, while adverse effects were classified as moderate, headaches were recorded in 14% of patients. Prolonged usage may diminish adherence, especially among demographics prioritizing ease and comfort over visual or surgical options. Furthermore, comparative analyses including multifocal lenses, corneal inlays, or refractive surgery are essential to ascertain the placement of pilocarpine drops among the array of possible therapies. Future research should prioritize long-term randomized controlled studies including real-world patient populations for wider therapeutic use. Patient-reported outcome measures (PROs), including visual satisfaction, functional independence, and quality of life. Investigation of individualized dosage strategies or combination treatments to enhance efficacy and tolerability, improve pupil dynamics, and reduce night-vision impairment. Safety assessments in individuals with narrow angles, incipient cataracts, or systemic comorbidities. Comparative efficacy of multifocal contact lenses, corneal inlays, or laser refractive alternatives. In conclusion, pilocarpine hydrochloride 1.25% presents a distinct and potentially advantageous pharmaceutical strategy for presbyopia. Nonetheless, caution is advisable prior to extensive clinical application. Addressing the identified research gaps will be crucial for establishing its long-term function in presbyopia therapy.