IHEEZO's 58% Discomfort Edge Over Proparacaine: Regulatory Path Clear, Payer Value Unproven

Harrow's IHEEZO Significantly Reduces Discomfort in Intravitreal Injections

Harrow announced positive results from a prospective, randomized, contralateral-eye study evaluating IHEEZO® (chloroprocaine hydrochloride ophthalmic gel) 3% for ocular surface anesthesia. The study, conducted in patients undergoing same-day bilateral intravitreal injections, demonstrated that IHEEZO significantly reduced patient-reported discomfort by approximately 58% overall compared to proparacaine ophthalmic solution 0.5%. Statistically significant differences favoring IHEEZO were observed at all measured time points, with the largest absolute differences occurring immediately after injection.

• The investigator-initiated study employed a rigorous contralateral-eye comparison design, involving 100 eyes from 50 adult patients. Each patient received both IHEEZO and proparacaine, allowing them to serve as their own control and minimizing between-patient variability, thereby strengthening the reliability of the comparative results.
• IHEEZO consistently demonstrated statistically significant reductions in patient-reported ocular discomfort across all four post-injection assessments (2 minutes, 1 hour, 6–12 hours, and 24 hours), with all p-values ≤0.048. The most pronounced benefits were seen shortly after injection, with absolute treatment differences of 1.62 points at two minutes and 1.56 points at one hour.
• These findings hold significant clinical relevance for retina specialists and patients, given that millions of intravitreal injections are performed annually, often requiring repeated treatments over extended periods. The measurable improvement in patient comfort with IHEEZO offers a differentiated clinical profile that could enhance the overall injection experience and support broader utilization in high-volume retina practices.

Addressing Patient Discomfort in Frequent Intravitreal Injections

Recent literature highlights a continued push toward optimizing ocular surface anesthesia — not only in terms of efficacy, but also tolerability and formulation design — particularly for patients undergoing high-volume or repeat ocular procedures. Clinical investigation has centered on identifying alternatives to traditional anesthetic eye drops that reduce procedural discomfort while maintaining a robust safety profile.

• Gel-based anesthetic formulations as a primary development focus: A multicenter randomized clinical trial in 338 patients evaluated chloroprocaine 3% gel versus tetracaine 0.5% eye drops in cataract surgery. Chloroprocaine gel achieved a 92.0% success rate (152/166 patients) in providing ocular surface anesthesia without supplementation, compared to 90.5% (153/172 patients) for tetracaine, demonstrating therapeutic equivalence. Mean onset was 1.35 ± 0.87 min versus 1.57 ± 1.85 min for tetracaine (P = 0.083), with comparable duration (21.57 ± 12.26 min vs. 22.04 ± 12.58 min; P = 0.574).

• Cataract surgery patients as the principal target population: Patients undergoing routine clear corneal phacoemulsification represent the primary population in recent ocular surface anesthesia research, with a clinical focus on achieving sustained anesthesia through the critical window just prior to intraocular lens implantation — without the need for anesthetic supplementation.

• Minimizing anesthetic-related ocular surface adverse effects: A key unmet need identified across recent studies is the reduction of procedure-associated discomfort attributed to the anesthetic agent itself. Safety endpoints have explicitly included pain, irritation, burning, stinging, photophobia, and foreign body sensation — underscoring demand for formulations that do not compromise ocular surface tolerability. Notably, no treatment-emergent adverse events related to chloroprocaine gel were reported in the referenced trial.

IHEEZO's Contralateral Study Design and Discomfort Reduction Results

The key clinical and preclinical trials evaluating ocular surface anesthesia span a range of designs, from prospective randomized controlled studies in cataract surgery patients to rodent corneal anesthesia models. These trials assessed both efficacy equivalence and novel agent performance across multiple endpoints including anesthesia onset, duration, depth, and tolerability.

IHEEZO's Differentiated Profile for Ocular Surface Anesthesia

Published studies comparing investigational ocular anesthetics to standard-of-care treatments reveal broadly comparable efficacy profiles, with differences emerging primarily in onset kinetics, duration of action, and tolerability. In a multicenter randomized trial of 338 cataract surgery patients, chloroprocaine 3% gel demonstrated equivalence to tetracaine 0.5% eye drops, with anesthesia success rates of 92.0% versus 90.5%, respectively (difference in proportions: 1.5%; 95% CI: −3.6 to 6.6). Onset of anesthesia was similar between arms (1.35 ± 0.87 min for chloroprocaine vs. 1.57 ± 1.85 min for tetracaine; P = 0.083), as was duration (21.57 ± 12.26 min vs. 22.04 ± 12.58 min; P = 0.574). No treatment-emergent adverse events attributable to chloroprocaine were observed, and local tolerance and vital sign findings were unremarkable across both arms. A retrospective safety analysis encompassing 166 healthy volunteers across six Phase 1 trials further reinforced a favorable tolerability signal, with 98% of reported adverse events classified as mild and all resolving by study end; laboratory evaluations and vital signs were within normal ranges in 88% of participants.

Lidocaine hydrochloride gel has been evaluated across a substantial body of prospective evidence — 15 randomized controlled trials (total N = 933) and 6 nonrandomized prospective studies (total N = 234) — consistently demonstrating at least equivalent pain control relative to comparator therapies, which included topical drops, subconjunctival anesthetic, retrobulbar anesthetic, and sham gel formulations. A key differentiator was its longer duration of action compared to topical drop formulations. Patient and surgeon satisfaction were reported as high across studies, and adverse effects were rare and comparable in frequency to those observed with anesthetic drop formulations.

Head-to-head comparisons among established topical agents reveal meaningful pharmacodynamic distinctions. In a 21-patient study evaluating proparacaine, tetracaine, and oxybuprocaine, corneal sensitivity decreased significantly within 30 seconds of application for all agents and returned to baseline by 30 minutes (P < 0.0001). Proparacaine demonstrated superior anesthetic effect at the 5-minute timepoint (P = 0.0003), whereas tetracaine produced the most pronounced effect at 10 minutes (P = 0.0135) and 20 minutes (P < 0.0001); however, tetracaine was also associated with the most intense burning sensation on instillation (P < 0.0001). A separate concentration-ranging study of proparacaine in 137 patients (274 eyes) found no statistically significant difference in intraoperative pain scores between 0.5% and 0.25% formulations (P = 0.66), with neither group requiring supplemental anesthesia and patient preference for repeat use exceeding 96% in both arms.

IHEEZO: Elevating Patient Comfort in Intravitreal Injections

The recent announcement regarding IHEEZO® (chloroprocaine hydrochloride ophthalmic gel) 3% marks a pivotal moment for patient comfort in ophthalmology, particularly for those undergoing intravitreal injections (IVIs). These injections are a cornerstone treatment for numerous sight-threatening conditions, and while highly effective, the procedure itself can be a source of significant anxiety and discomfort for patients. The finding that IHEEZO significantly reduced patient-reported discomfort by approximately 58% compared to proparacaine, a widely used topical anesthetic, is a compelling development.

This substantial improvement in patient experience could redefine the standard of care for ocular surface anesthesia in IVIs. For pharmaceutical companies, this positions IHEEZO as a strong contender to capture market share in a high-volume segment. The drug's versatility is further underscored by previous studies demonstrating its efficacy and safety in cataract surgery, suggesting a broad utility across various ophthalmic procedures. By addressing a critical unmet need for enhanced comfort, IHEEZO could not only improve patient satisfaction but also potentially boost adherence to long-term treatment regimens, which is crucial for managing chronic eye diseases.

However, several factors warrant consideration. While IHEEZO's overall discomfort reduction is impressive, existing evidence suggests that proparacaine offers a rapid onset and comfortable instillation, which might retain a niche preference among some clinicians or patients. Furthermore, as a novel gel formulation, IHEEZO's pricing relative to generic alternatives could influence its widespread adoption. Finally, while current data indicates a favorable safety profile, continuous real-world monitoring will be essential to fully understand its long-term tolerability and identify any less common adverse events in a broader patient population. Ultimately, IHEEZO has the potential to significantly elevate the patient experience in ophthalmic care, setting a new benchmark for topical anesthesia.