Comparison of Proparacaine, Tetracaine, and Oxybuprocaine in Corneal Sensitivity Measurement.

Purpose: This study aimed to determine the onset and duration of action of 3 commercially available topical anesthetic solutions in Brazil, using the Cochet-Bonnet esthesiometer (Luneau®, Paris, France) and to quantitatively assess patient-reported discomfort during application. Methods: A prospective, randomized, masked, and double-blind study was conducted, involving 40 eyes from 21 patients. Patients were administered each one of the topical anesthetics weekly, and corneal sensitivity was measured using the Cochet-Bonnet esthesiometer's corneal touch threshold (CTT). Patients rated the burning sensation using a visual analogue scale (VAS). Results: Among the 21 patients (42.9% male), with a mean age of 31.95 years (±standard deviation = 10.17, range = 22.0-58.0), corneal sensitivity significantly decreased 30 s after application, returning to baseline after 30 min for all groups (P < 0.0001). Significant differences in CTT were observed at 5 min, with proparacaine exhibiting a superior anesthetic effect (P = 0.0003), at 10 min, where tetracaine displayed the most substantial anesthetic effect (P = 0.0135), and at 20 min, where tetracaine demonstrated the highest anesthetic efficacy (P < 0.0001). VAS scores indicated the most intense burning sensation with tetracaine (P < 0.0001). Men reported experiencing more discomfort during instillation compared with women (P = 0.0168). Conclusions: Proparacaine exhibited the fastest onset of action among the 3 topical anesthetics and provided a more comfortable eye sensation during instillation. However, tetracaine demonstrated the longest duration of action despite causing more discomfort.

Proparacaine Overuse in Corneal Abrasions at the Emergency Department: A Case Series.

ABSTRACT: Corneal abrasions are among the most common ophthalmic injuries in the emergency department (ED) and primarily present as severe ocular pain. Topical anesthetics provide temporary analgesia, but overuse is associated with complications including further corneal injury, infection, and vision loss. This case series describes three patients who used a 15-mL bottle of 0.05% proparacaine hydrochloride ophthalmic solution after discharge from the ED and returned within three days with corneal injury and pain. Although the use of topical anesthetics is traditionally discouraged by ophthalmologists, publications in the emergency medicine literature support their use. We review the literature surrounding topical anesthetic use in the ED setting and caution against prescribing patients topical anesthetics for corneal abrasions, particularly without patient counseling and significant restriction of anesthetic supply.

Revisiting rabbit models for keratoconus: A long-term study on collagenase-induced disease progression.

Keratoconus (KC) is a degenerative disorder resulting from the degradation of the stromal collagen fibril network in the cornea, leading to its thinning and conical deformation. Various studies have established animal models of KC by using the collagenase type II enzyme to gain a better understanding of the pathogenesis, however, long-term monitoring or follow-up of the models have not been reported so far. This study evaluates the long-term stability of collagenase type II-induced KC in a rabbit model. Six New Zealand rabbits were divided into 4 study groups with 3 eyes per group. The groups were control (group 1), 0.5% proparacaine + 5 min collagenase treatment on day 0 and day 30 (group 2), 0.5% proparacaine + 10 min collagenase treatment on day 0 (group 3) and, mechanical debridement + 2 min collagenase treatment on day 0 (group 4). Inflammation was observed in group 4 till week 10. Significant decrease in the central corneal thickness was observed in group 3 by week 4 (p < 0.001) however, the thickness was regained in the subsequent follow-ups in all the groups. Keratography results showed no changes in Km values but an increased astigmatic power in all groups. Scanning electron microscopy images revealed thinner collagen fibrils arranged in a mesh-like pattern above the uniform layer of the collagen lamellae in the central part of the treated corneas. Similarly, histological staining revealed loosely packed stromal fibrils in the anterior portion of the cornea which corroborates with the immunofluorescent staining results. This study revealed the remodeling of the corneal structure by eight weeks of collagenase treatment. Consequently, the possibility of creating a rabbit keratoconus model induced by collagenase may warrant further consideration.

Comparison of cycloplegia at 20- and 30-minutes following proxymetacaine and cyclopentolate instillation in white 12-13-year-olds.

CLINICAL RELEVANCE: Reducing the time between drop instillation and refraction reduces the time paediatric patients and young adults spend in practice, facilitating more eye examinations daily. BACKGROUND: The current procedure for paediatric cycloplegic refraction is to wait for at least 30-minutes post-instillation of a cycloplegic before measuring spherical equivalent refraction. This study compared cycloplegia at 20- and 30-minutes following 0.5% proxymetacaine and 1.0% cyclopentolate in 12-13-year-olds. METHODS: Participants were 99 white 12-13-year-olds. One drop of proxymetacaine hydrochloride (Minims, 0.5% w/v, Bausch & Lomb, UK) followed by one drop of cyclopentolate hydrochloride (Minims, 1.0% w/v, Bausch & Lomb, UK) was instilled into both eyes. Spherical equivalent refraction was measured by autorefraction (Dong Yang Rekto ORK-11 Auto Ref-Keratometer) at 20- and 30-minutes post-instillation. Data were analysed through paired t-testing, correlations, and linear regression analysis. RESULTS: There was no significant difference in level of cycloplegia achieved at 20- (Mean spherical equivalent refraction (standard deviation) 0.438 (1.404) D) and 30-minutes (0.487 (1.420) D) post-eyedrop instillation (t (98) = 1.667, p = 0.099). The mean spherical equivalent refraction difference between time points was small (0.049 (0.294) D, 95% confidence interval =-0.108 ̶ 0.009D). Agreement indices: Accuracy = 0.999, Precision = 0.973, Concordance = 0.972. Spherical equivalent refraction at 20- and 30-minutes differed by ≤0.50D in 92% of eyes, and by <1.00D in 95%. CONCLUSIONS: There was no clinically significant difference in spherical equivalent refraction or level of cycloplegia at 20- and 30-minutes post-eyedrop instillation. The latent time between drop instillation and measurement of refractive error may be reduced to 20 minutes in White 12-13-year-olds and young adults. Further studies must determine if these results persist in younger children and non-White populations.

Effect of Topical Anesthesia on Reducing Pain Associated with Mydriatic Eye Drops during Retinopathy of Prematurity Screening.

INTRODUCTION: The study aimed to investigate the effectiveness of topical anesthetic drops in reducing the pain associated with mydriatic eye drops prior to the retinopathy of prematurity (ROP) examination. METHODS: Premature infants who underwent first-time ROP examinations in an outpatient setting were included in this randomized controlled trial. The study group included the infants who were administered topical anesthesia prior to the first mydriatic drops, and the control group included the infants who were given preservative-free artificial tear drops. Pain assessment was performed using the premature infant pain profile (PIPP). RESULTS: A total of 66 infants, 35 in the control group and 31 in the study group, were included in the study. The PIPP scores of the infants during the first, second, and third mydriatic drops were 5.3 ± 2.0; 4.9 ± 1.7; and 4.0 ± 1.8, respectively, in the study group and 5.3 ± 1.7; 5.6 ± 1.8; and 4.6 ± 1.8, respectively, in the control group. No significant difference was found in the scores between the two groups. The PIPP score after the third drop was significantly lower than that after the second drop in the control group, and the PIPP score after the third drop was significantly lower than that obtained after the first and second drops in the study group. DISCUSSION/CONCLUSION: This study showed no significant benefit of the topical anesthetic drop in the prevention of pain associated with mydriatic eye drops. The decrease in the pain response observed in repeated administrations is a novel finding.

Effects of Regular/Dilute Proparacaine Anesthetic Eye Drops in Combination with Ophthalmic Antibiotics on Corneal Wound Healing.

Purpose: Topical, local anesthetic eye drops in conjunction with antibiotics are commonly used to reduce ocular pain and treat patients in emergency clinics; however, their effects on corneal healing are poorly understood. This study examined whether regular or diluted proparacaine eye drops given in combination with common ophthalmic antibiotics affect corneal wound healing parameters using in vitro and in vivo models. Methods: Primary human corneal fibroblasts generated from donor corneas and New Zealand white rabbits were used. Regular (0.5%) and diluted (0.05%) proparacaine eye drops, twice daily for 3 days, were applied to cultures and rabbit eyes, with or without ophthalmic antibiotics (polymyxin B sulfate and trimethoprim). Trypan blue, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), and scratch wound assays measured cellular viability, proliferation, and migration, respectively, in vitro. Slit lamp biomicroscopy, tonometry, fluorescein eye test, hematoxylin and eosin (H&E) staining, and 4',6-diamidino-2-phenylindole (DAPI) immunofluorescence were used for in vivo studies. Results: Both regular and diluted proparacaine affected wound healing response in the cornea in vitro and in vivo in a time-dependent manner. Adjunct antibiotic treatments had additive effects characterized by reduced corneal fibroblast viability, proliferation, and migration in vitro and corneal epithelial recovery in vivo. Regular proparacaine with antibiotics showed most pronounced effects on corneal wound healing parameters, and diluted proparacaine without antibiotics had minimal negative effects in vitro and in vivo. Conclusion: Both methods of regular (0.5%) and diluted (0.05%) proparacaine topical application to the cornea are safe, but impede corneal wound healing in vitro and in vivo. Adjunct antibiotic treatments had additive negative effects on corneal wound repair.

The effect of topical ophthalmic proparacaine, fluorescein, and tropicamide on subsequent bacterial cultures in healthy dogs.

OBJECTIVE: To determine whether tropicamide, fluorescein, and proparacaine applied topically before sample collection affect the quantity or species of bacteria isolated via aerobic culture. ANIMALS STUDIED: 12 female adult research beagle cross-breed dogs. PROCEDURES: A conjunctival swab was taken before and after the sequential application of proparacaine, tropicamide, and fluorescein to the same eye (P/T/F) with a five-minute gap between medications. Paired swabs were submitted for aerobic culture. Bacterial enumeration was performed using the spread plate method. Following a one-week washout period, the procedure was repeated using balanced salt solution (BSS). Following a second one-week washout period, the experiment was repeated using ofloxacin 0.3% solution. Colony counts were compared using one-way ANOVA and Tukey post hoc comparison. Bacterial species reduction was compared using a Friedman rank test and Dunn's method. RESULTS: The bacterial colony count for P/T/F and BSS was significantly higher than the ofloxacin group (p = 0.0052, p = 0.0022). There was no significant difference for colony counts between P/T/F and BSS (p = 0.9295). The most frequently isolated bacteria included: Psychrobacter spp., Staphylococcus spp., Corynebacterium spp., and Streptococcus spp. The bacterial species reduction for P/T/F and BSS was significantly lower than for ofloxacin (p < 0.0001, p = 0.0160). There was no significant difference for species reduction between P/T/F and BSS (p = 0.3749). CONCLUSIONS: The application of proparacaine, tropicamide, and fluorescein did not significantly decrease the amount or species of bacteria isolated from the conjunctiva in this canine population. The application of these solutions prior to ocular swab collection in healthy dogs is unlikely to affect subsequent culture results.

The effect of brimonidine and proparacaine on metabolic enzymes: Glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and glutathione reductase.

Oxidative stress is to upregulate the pentose phosphate pathway (PPP). The PPP consists of two functional branches, glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconaste dehydrogenase (6PGD). Glutathione reductase (GR) has a significant role in catalyzing an oxidized glutathione form into a reduced form. The purpose of this study is to investigate the effects of brimonidine and proparacaine on the activity of 6PGD, G6PD, and GR enzymes purified from human erythrocytes. Brimonidine displayed considerable inhibition profile against G6PD with IC50 value and KI constant of 29.93 ± 3.56 and 48.46 ± 0.66 µM, respectively. On the other hand, proparacaine had no inhibitory effect against G6PD. KI values were found to be 66.06 ± 0.78 and 811.50 ± 11.13 µM for brimonidine and proparacaine, respectively, for 6PGD. KI values were found to be 144.10 ± 2.01 and 1,654.00 ± 26.29 µM for brimonidine and proparacaine, respectively, for GR. Herein, also in silico molecular docking studies were performed between drugs and enzymes.

New application of an old drug proparacaine in treating epilepsy via liposomal hydrogel formulation.

Proparacaine (PPC) is a previously discovered topical anesthetic for ophthalmic optometry and surgery by blocking the central Nav1.3. In this study, we found that proparacaine hydrochloride (PPC-HCl) exerted an acute robust antiepileptic effect in pilocarpine-induced epilepsy mice. More importantly, chronic treatment with PPC-HCl totally terminated spontaneous recurrent seizure occurrence without significant toxicity. Chronic treatment with PPC-HCl did not cause obvious cytotoxicity, neuropsychiatric adverse effects, hepatotoxicity, cardiotoxicity, and even genotoxicity that evaluated by whole genome-scale transcriptomic analyses. Only when in a high dose (50 mg/kg), the QRS interval measured by electrocardiography was slightly prolonged, which was similar to the impact of levetiracetam. Nevertheless, to overcome this potential issue, we adopt a liposome encapsulation strategy that could alleviate cardiotoxicity and prepared a type of hydrogel containing PPC-HCl for sustained release. Implantation of thermosensitive chitosan-based hydrogel containing liposomal PPC-HCl into the subcutaneous tissue exerted immediate and long-lasting remission from spontaneous recurrent seizure in epileptic mice without affecting QRS interval. Therefore, this new liposomal hydrogel formulation of proparacaine could be developed as a transdermal patch for treating epilepsy, avoiding the severe toxicity after chronic treatment with current antiepileptic drugs in clinic.

Assessing the Clinical Requirement of 2.5% Phenylephrine for Diagnostic Pupil Examination.

Purpose: To evaluate whether the standard dilating drop regimen consisting of phenylephrine, tropicamide, and proparacaine produces clinically significant improvement in pupil size compared to tropicamide and proparacaine during diagnostic eye examination. Methods: Sixty-three adult patients at Washington University School of Medicine Eye Clinic were enrolled in this prospective, randomized trial. Each patient received one of two dilating drop regimens: phenylephrine + tropicamide + proparacaine (PE+T+PP), which is considered the standard therapy, or tropicamide + proparacaine (T+PP). Main outcome measures were the proportion of pupils able to achieve successful clinical examination without need for additional dilating drops and change in predilation to postdilation pupil size. Comparisons were made using McNemar's test, repeated measures analysis of variance, and Fisher's test to determine whether PE is a necessary component of the standard eye examination. Results: There were no statistically significant differences between the PE+T+PP and T+PE treatment groups in predilation to postdilation changes in average resting pupil size (1.58 ± 0.66 and 2.61 ± 0.79; P = 0.57) or constricted pupil size (2.52 ± 0.93 and 3.56 ± 0.96; P = 0.15). There was no statistically significant difference between patients who obtained a successful dilated pupil examination between those receiving PE+T+PP and those receiving T+PP as determined by the examining physicians (Fisher's, P = 0.67). Conclusion: The addition of phenylephrine to tropicamide and proparacaine did not improve pupillary dilation size or ability to conduct a clinical examination. A single dilating agent using tropicamide should be considered in clinical practice.

REPLACEMENT OF LIDOCAINE GEL WITH TOPICAL PROPARACAINE ANESTHESIA FOR ROUTINE INTRAVITREAL INJECTIONS: A Comparative Study.

PURPOSE: Lidocaine gel was suggested to be highly effective in providing anesthesia for intravitreal injections but adverse effects include a possibility of making sterilization of the conjunctiva difficult. Hence, we wished to determine the effect of using 0.5% proparacaine drops alone over the use of 3.5% lidocaine hydrochloride gel anesthesia during office-based intravitreal injections. METHODOLOGY: This was a case-control study in patients who came routinely to the clinic for antivascular endothelial growth factor injections. Eyes were treated with one of two anesthesia modalities. A total of 216 injections in 120 patients were reviewed. One group (N = 107) underwent anesthesia with 0.5% proparacaine drops, and the control group (N = 109) received 3.5% lidocaine gel. The pain perceived after injection was graded using the numerical rating scale, and score was immediately recorded by the "masked" injecting physician. RESULTS: The mean pain score (±SD) for the proparacaine-only group versus gel group was 1.97 (±1.17) versus 1.76 (±0.92), P value = 0.3174. There was no statistical difference between the 2 groups. CONCLUSION: 3.5% lidocaine gel is not superior to 0.5% proparacaine drops as patients attained good pain control and excellent rates of overall satisfaction with proparacaine drops alone.

Effects of topical application of tramadol with/without dexmedetomidine and proparacaine on corneal sensitivity in rats.

PURPOSE: To evaluate the corneal anesthetic effect following topical application of tramadol alone and in combination with dexmedetomidine, and compare it to proparacaine, in clinically healthy rats. METHODS: A randomized, crossover study was performed. Twenty Wistar albino rats (n = 40 eyes) were used. Corneal touch threshold (CTT) measurements (in mm) were obtained using a Cochet-Bonnet aesthesiometer. CTT measurements were obtained at baseline, 1-min following application of the topical anesthetic agent, and repeated at 5-min intervals up to 75 min. The topical protocol involved 3 treatment conditions, separated by a 2-week washout period: proparacaine, tramadol alone, and tramadol in combination with dexmedetomidine. RESULTS: CTT values were significantly decreased compared to baseline at each timepoint until completion of the 75-min evaluation in all treated eyes, regardless of the assigned treatment (p < 0.0083). With tramadol, complete corneal anesthesia (CTT = 0) was achieved within 1-5 min in 18 eyes and ranged from 5 to 25 min. Co-administration of dexmedetomidine to tramadol resulted in significantly increased CTT values from 5 to 20 min following topical application, compared to tramadol alone (p < 0.0083), and complete corneal anesthesia was achieved in only 14 out of 20 treated eyes. CONCLUSION: Tramadol might be a useful alternative to topical anesthetic agents, providing a dose-related corneal anesthetic effect. Co-administration of dexmedetomidine does not potentiate its anesthetic effect. The underlying mechanism(s) of drug antagonism between tramadol and dexmedetomidine remains to be determined.

Identification, synthesis and structural confirmation of process-related impurities in proparacaine hydrochloride.

Proparacaine hydrochloride is an ester-type local anesthetic agent that is extensively used in ophthalmic operations. The process-related impurities of proparacaine hydrochloride were investigated, and seven impurities were detected in the reaction solution of the last step at the level of 0.03-1.08 % by a newly developed HPLC method. Based on the synthetic process and the results of LC-HRMS, the structures of five impurities were proposed as 3-amino-4-propoxybenzoic acid (Imp-A), ethyl 3-amino-4-propoxybenzoate (Imp-B), 2-(ethylamino)ethyl 3-amino-4-propoxybenzoate hydrochloride (Imp-C), 2-(diethylamino)ethyl 3-nitro-4-propoxybenzoate hydrochloride (Imp-F), and 3-nitro-4-propoxybenzoic acid (Imp-G). And the structures were confirmed by synthesis, followed by varieties of spectral and chromatographic analyses. The structures of two impurities with almost same molecular weight in LC-HRMS were elucidated as 2-(diethylamino)ethyl 3-(ethylamino)-4-propoxy-benzoate hydrochloride (Imp-D) and 2-(diethylamino)ethyl 3-formamido-4-propoxybenzoate hydrochloride (Imp-E) by NMR and IR. An HPLC-based method was developed, and validation study demonstrated that the approach was precise, accurate, and sensitive. The impurities information of proparacaine hydrochloride can be used for the quality control of intermediate, raw material drug and its commercial products.

Topical proparacaine eye drops to improve the experience of patients undergoing intravitreal injections: A randomized controlled trial.

PURPOSE: We sought to evaluate whether additional topical anesthetic, specifically proparacaine 0.5%, improved patient experience with intravitreal injections without hindering antisepsis. METHODS: A prospective, randomized controlled trial was conducted including 36 eyes of 36 patients undergoing intravitreal injections. Patients were randomized to treatment with additional topical proparacaine 0.5% versus control after undergoing informed consent. All patients prior to intravitreal injection underwent conjunctival culture after one drop of topical proparacaine 0.5% was placed. Half of patients then received an additional drop of proparacaine and then underwent a second conjunctival culture. The other half of patients had a drop of povidone iodine and then a second conjunctival culture. Intravitreal injection followed conjunctival cultures. To evaluate their experience, patients were provided with a survey. RESULTS: In total, 36 patients were enrolled in the study. Three of 36 (8.3%) patients had positive conjunctival cultures after proparacaine eye drops alone. One of 17 (5.8%) patients had a positive conjunctival culture after a second drop of proparacaine. One of 19 (5.3%) patients had a positive culture after proparacaine and povidone iodine. By noninferiority analysis, proparacaine was inferior to povidone iodine (p = .28). Patient experience surveys did not differ between groups. CONCLUSION: Patient perception did not significantly differ whether or not additional proparacaine drops were used prior to intravitreal injection in a randomized controlled trial. While proparacaine has some antiseptic properties, these were found to be inferior to those of povidone iodine. Therefore, while povidone iodine is essential for antisepsis, additional proparacaine drops should not interfere with antisepsis.

Postoperative Corneal Injuries: Incidence and Risk Factors.

BACKGROUND: Previous studies of postoperative corneal injury rates relied on provider-initiated incident reports, which may underestimate the true incidence. Postoperative administration of proparacaine eye drops is used almost exclusively to diagnose corneal injury; therefore, identifying instances of administration may provide a better estimate of corneal injuries. We compared proparacaine administration versus provider-initiated reports to determine rates of corneal injury. In addition, potential associations between clinical variables and injury were assessed with a matched case-control study. METHODS: The health records of 132,511 sequential adult postanesthesia recovery room admissions (January 1, 2011 to June 30, 2017) were reviewed to identify postoperative proparacaine administration and incident reports of corneal injury. Patients with corneal injury were matched with control patients at a 1:2 ratio to assess factors associated with injury. RESULTS: Proparacaine drops were administered to 442 patients (425 patients received proparacaine for diagnosis and 17 patients received proparacaine for unrelated reasons). Incident reports identified 320 injuries, and the aggregate corneal injury count was 436 (incidence, 3.3 injuries [95% confidence interval {CI}, 3.0-3.6] per 1000 cases of general anesthesia). Proparacaine administration had a greater case ascertainment percentage than incident reporting (97.5% vs 73.4%; P < .001). The matched case-control analysis found greater risks associated with longer duration of anesthesia (odds ratio, 1.05 [95% CI, 1.03-1.07] per 10 minutes of anesthesia; P < .001) and nonsupine surgical position (odds ratio, 3.89 [95% CI, 2.17-6.98]; P < .001). Patients with injuries also had more evidence of sedation and agitation during anesthesia recovery. CONCLUSIONS: Calculation of incidence by using the administration of a medication (proparacaine eye drops) that is almost exclusively used to diagnose a specific injury (corneal injury) showed higher case ascertainment percentage than incident-reporting methods. Similar strategies could be used to monitor the rates of other adverse events.

Serotonin enhances oxybuprocaine- and proxymetacaine-induced cutaneous analgesia in rats.

The aim of the study was to investigate the analgesic effects of adding serotonin to oxybuprocaine or proxymetacaine preparations. We employed a rat model of the cutaneous trunci muscle reflex (CTMR) to conduct the dose-response curves and duration of drugs (oxybuprocaine, proxymetacaine, or serotonin) as an infiltrative anesthetic. The use of isobolographic methods to analyze the drug-drug interactions. We showed that oxybuprocaine and proxymetacaine, as well as serotonin produced dose-dependent skin antinociception. On the basis of 50% effective dose (ED50), the rank order of drug potency was serotonin [7.22 (6.45-8.09) µmol/kg] < oxybuprocaine [1.03 (0.93-1.15) µmol/kg] < proxymetacaine [0.59 (0.53-0.66) µmol/kg] (P < 0.01 for each comparison). The sensory block duration of serotonin was longer (P < 0.01) than that of oxybuprocaine or proxymetacaine at the equipotent doses (ED25, ED50, and ED75). The mixture of serotonin with oxybuprocaine or proxymetacaine produced a better analgesic effect than the drug itself. We have concluded that oxybuprocaine, proxymetacaine, or serotonin displays dose-related cutaneous analgesia. Oxybuprocaine or proxymetacaine is more potent and has a shorter duration of cutaneous analgesia than serotonin. Serotonin produces a synergistic antinociceptive interaction with oxybuprocaine or proxymetacaine.