Topical Ophthalmic Anesthetics for Corneal Abrasions: Findings from a Cochrane Systematic Review and Meta-Analysis

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An unbiased analysis of randomized controlled trials (RCTs) is needed to examine their effectiveness and safety compared with placebo or other treatments for corneal abrasions. Methods Cochrane Central Register of Controlled Trials, MEDLINE, Embase.com, Latin American and Caribbean Health Sciences, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched on February 10, 2023, without restriction on language or publication date. Results Systematic review and meta-analysis of nine RCTs describing 314 participants with post-traumatic abrasions and 242 participants with post-surgical abrasions, with a median study length of 7 days (interquartile range, 7–14), show no evidence of a difference in pain control between anesthetics and placebo at 24 hours in post-trauma cases. Self-reported pain at 24 hours is reduced with anesthetics plus topical nonsteroid anti-inflammatory drug in post-surgical participants (mean difference [MD], -5.72 on a 10-point scale; 95% CI, -7.35 to -4.09; 1 RCT; 30 participants) and at 48 hours with anesthetics alone in post-trauma participants (MD, -5.68; 95% CI, -6.38 to -4.98; 1 RCT; 111 participants). Anesthetics are associated with 37% increased risk of non-healing defects (risk ratio, 1.37; 95% CI, 0.78 to 2.42; 3 RCTs; 221 post-trauma participants). All evidence is of very low certainty. Over 50% of trials have an overall high risk of bias. Conclusions Available evidence is insufficient to support outpatient use of topical anesthetics for corneal abrasions with respect to pain, re-epithelialization, and complication risk. Health sciences/Signs and symptoms Health sciences/Medical research corneal injuries corneal abrasion eye pain local anesthetics corneal epithelium emergency room visits Figures Figure 1 Figure 2 Figure 3 Figure 4 PLAIN LANGUAGE SUMMARY The cornea, the clear, dome-shaped structure covering the iris, is one of the most pain-sensitive tissues in the body. Traumatic abrasions (disruption of the epithelium, the top corneal layer) account for > 10% of all eye-related visits to emergency rooms in the US. Epithelial removal also occurs in some eye surgeries. Topical anesthetic drops for corneal abrasions are controversial; they can be habit-forming and can cause corneal scar or blindness. Nonetheless, a growing number of emergency department providers prescribes these drops for corneal abrasions, despite the fact most heal within days. By carefully analyzing 9 randomized controlled trials, we do not find enough evidence that topical anesthetics reduce pain, improve healing, or decrease the chance of complication compared with placebo. INTRODUCTION Corneal abrasions, loss of the corneal epithelium, can occur from trauma, ocular surgery, dryness, and exposure. They account for 13% of eye-related emergency department visits in the US, with an annual incidence of 3 per 1000 persons and a higher male prevalence. 1–3 Traumatic abrasions present with symptoms like pain, photophobia, redness, and tearing. As the cornea is one of the most highly innervated tissues in the body, corneal nociceptors, especially mechanoreceptors, contribute to intense eye pain until healing occurs. Although most small to medium-sized corneal abrasions heal within a few days, complications like corneal erosions and infection may require medical or surgical intervention. In contrast, post-surgical corneal epithelial defects benefit from a sterile field and controlled wound construction. In medicine, topical nonsteroidal anti-inflammatory drugs (NSAIDs) and anesthetic drugs are used for localized analgesia with limited systemic effects. However, numerous case reports describe ophthalmic complications from use of high concentrations of topical anesthetics, at excessive frequency, or for prolonged periods of time, including corneal infiltrate, stromal keratolysis (“melt”), endothelial injury, and perforation 4–21 – all of which can lead to vision loss. Recent emergency department studies have deemed outpatient use of prescribed topical anesthetics as safe and effective for corneal abrasions. 22–24 This assessment contrasts with the experience of ophthalmologists, 6–23 leading to renewed questions about outpatient anesthetic use. The lack of consensus guidelines may account for variations in practice within and across specialties. 25–27 The main objective of this summary of our Cochrane systematic review is to report the comparative effectiveness and safety of topical ophthalmic anesthetics compared with placebo or other treatments for corneal abrasions of any etiology, based on the best available evidence. 28 In nine eligible randomized controlled trials (RCTs) describing 556 participants with corneal abrasions from traumatic or surgical origin, we find insufficient evidence to support outpatient use of topical ophthalmic anesthetics compared with placebo for reducing pain, improving re-epithelialization, or reducing complication risk in corneal abrasions. METHODS Eligibility criteria for studies and outcomes of interest : We examined only randomized controlled trials (RCTs). Eligible trials compare topical ophthalmic anesthetics (amide or ester class) with a control group (placebo, non-treatment, or alternative treatment). Trials in which topical anesthetics with an NSAID were compared with a control group were eligible. We considered trials that enrolled participants of all ages with corneal abrasions within 48 hours of presentation from accidental trauma or ophthalmic surgery. The primary review outcomes were ( 1 ) mean reduction in self-reported pain on a visual analog scale (VAS), where smaller numbers represent less pain, at 24, 48, and 72 hours after treatment initiation; ( 2 ) the proportion of participants without complete resolution of epithelial defects by 24–72 hours; and 3) the proportion of participants with adverse events (e.g. microbial keratitis or stromal infiltration, corneal stromal thinning, corneal perforation, surgical interventions) reported at the longest follow-up time of the study. For secondary outcomes, we considered treatment failure (the proportion of participants who required rescue oral analgesics by 72 hours after treatment initiation) and quality of life assessed by a validated instrument at the longest follow-up time of the study. Trials were not excluded on the basis of outcome reporting. Search methods for identifying studies : We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase.com, ClinicalTrials.gov ( www.clinicaltrials.gov ), and the WHO International Clinical Trials Registry Platform (ICTRP) ( www.who.int/ictrp/search/en ) to identify potentially eligible RCTs for this review. We did not impose restrictions on the search date or language of publication. The last date of search was February 10, 2023. Study selection: Pairs of review authors worked independently to review titles and abstracts as well as full-text records against the eligibility criteria; disagreements were resolved by discussion. Data collection and risk of bias: Authors independently extracted the following data from included studies: trial characteristics, methods, participants, interventions, outcomes, and source of funding. Two review authors independently applied the Cochrane's Risk of Bias version 2 (RoB2) tool 29 to assess risk of bias in the efficacy outcome (pain control by 48 hours) and the safety outcome (complications at the longest follow-up time). We judged each study that reported either outcome to have been at “low risk,” “high risk” or raising some concerns for risk of bias. An overall Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment of the certainty level of evidence was performed based on four main criteria: risk of bias, inconsistency, indirectness, and imprecision. 30 Disagreements were resolved by discussion within the author team. Data analysis and synthesis: For the continuous outcome of pain assessment, we estimated the difference in means (“mean difference”) (MD) with 95% confidence intervals (CI). For dichotomous outcomes, we estimated the risk ratios (RR) with 95% CI. We estimated the risk difference (RD) with 95% CI for trials reporting no events in either treatment group. 31 To determine whether results could be combined in meta-analyses, we assessed the trials for clinical and methodological heterogeneity in trial design, eligibility of trial participants, intervention and comparator differences, and outcome definitions. 32,33 We evaluated the amount of statistical heterogeneity using the I 2 statistic outlined in the Cochrane Handbook. 33 RESULTS We present analysis of nine RCTs (21 study reports) after a literature search yielded 7641 unique titles and abstracts that were screened, of which we reviewed 39 potentially relevant full-text publications (Fig. 1). Our quantitative analysis includes 8 of the 9 RCTs. One trial does not report data in a manner amenable to analysis for our specified outcomes. 34 All included trials are parallel-group, 2-arm RCTs, except for one 7-arm trial. 35 The trials span across eight countries from 1994 to 2021. The four post-traumatic abrasion trials were conducted in emergency departments. Four trials did not receive industry funding; funding information is unknown for five trials. 34–38 The included trials report data from 626 eligible participants who were randomized. After selecting the appropriate 3 arms from a 7-arm trial, 35 we analyzed 556 participants with a median of 45 participants per trial (interquartile range [IQR], 44–74; 9 RCTs). A higher proportion of women are enrolled in surgical trials (60%; 166/278 participants; 4 RCTs) than in post-trauma settings (21%; 65/314 participants; 4 RCTs). The following topical anesthetics are compared with placebo (Table 1): tetracaine 1% (2 RCTs), 23,39 0.5% (1 RCT), 22 and 0.4% (1 RCT); 40 proparacaine 0.05% (3 RCTs); 34,35,38 and lidocaine 2% (1 RCT). 36 One multi-arm trial compares proparacaine 0.05% and proparacaine 0.05% with topical diclofenac 0.1% against placebo. 35 One trial has an NSAID active control (diclofenac 0.1%). 37 When reported, the total amount of topical anesthetic dispensed by emergency departments ranges from 1.5 mL to 40 mL (approximately 30–800 drops). Four studies analyze abrasions of traumatic etiology in 314 participants (314 eyes). 22,23,38,40 Most abrasions involve corneal foreign bodies (47%; 148 eyes) or direct trauma (19%; 61 eyes). Five studies describe 242 participants (256 eyes) with post-surgical corneal defects, four from photorefractive keratectomy (PRK) 34,35,37,39 and one from pterygium surgery. 36 Overall, the median study length is 7 days (IQR, 7–14 days) with a median of 11 days (IQR, 7–18 days) for post-trauma trials and 7 days (IQR, 3–7 days) for post-surgical trials. Overall, the median treatment duration is 24 hours (IQR, 24–168 hours) with a median of 36 hours (IQR, 24–78 hours) for post-trauma trials and 24 hours (IQR, 24–168 hours) for post-surgical trials. Two (67%) of the three trials describing ocular pain results have an overall high risk of bias. Five (71%) of the seven trials describing ocular complications have an overall high risk of bias, primarily from missing outcome data and selective reporting of results. Effectiveness and safety of interventions Critical outcomes Pain control from baseline to 24 hours after treatment initiation The combined estimate for pain scores reported by post-surgical participants 35,36,39 suggests that when compared with placebo, topical anesthetics reduce pain by 1.28 on a 10-point VAS (MD, -1.28; 95% CI, -1.76 to -0.80; 3 RCTs; 119 participants; Fig. 2). In contrast, one post-PRK trial reports 0.82 higher pain scores on a 10-point VAS with tetracaine compared with NSAID (MD, 0.82; 95% CI, 0.01 to 1.63; 74 participants; Fig. 2). 37 No evidence of a difference in pain control (MD, -0.04; 95% CI, -0.10 to 0.02) is found in a trial using a mixed-model to account for multiple measurements, to which 76 (62%) of 122 of post-trauma participants contributed data. 23 One post-surgical trial compares an anesthetic plus an NSAID with placebo. 35 The estimated difference in means in reduction in pain scores (i.e., the “mean difference” or MD) from this study indicates anesthetic plus NSAID reduces pain scores at 24 hours when compared with placebo (MD, -5.72 on a 10-point scale; 95% CI, -7.35–-4.09; 30 participants). The certainty of evidence for all effect estimates is very low because of potential risk of bias and imprecision. Pain control from baseline to 48 hours after treatment initiation Using a 10-point VAS, post-surgical participants of one trial report little pain control relative to placebo (MD, 0.41; 95% CI, -0.45 to 1.27; 44 participants. 39 Post-trauma participants in one trial report 5.68 lower pain scores with tetracaine 0.5% than placebo (MD, -5.68; 95% CI, -6.38 to -4.98; 111 participants). 22 One post-trauma trial is excluded from this analysis because 57% of 124 randomized participants are lost to follow up. 23 The overall certainty of evidence is very low because of a high risk of bias, imprecision, and inconsistency across studies. No trial records pain control from baseline to 72 hours after treatment initiation. Epithelial healing by 24 to 72 hours In three post-trauma trials 22,23,40 the risk of persistent epithelial defects assessed at 24 to 72 hours is 37% higher with varying concentrations of tetracaine compared with placebo (RR, 1.37; 95% CI, 0.78 to 2.42; 3 RCTs; 221 participants; I 2 = 0%; Fig. 3). However, a decrease in the proportion of participants with persistent defects is found in a trial of 30 post-surgical participants using proparacaine 0.05% (RR, 0.14; 95% CI, 0.01 to 2.55; Fig. 3) and proparacaine 0.05% plus diclofenac 0.1% (RR, 0.33; 95% CI, 0.04 to 2.85), compared with placebo. 35 Overall, there is no evidence of differences although the evidence is of very low certainty because of a high risk of bias, inconsistency, and imprecision. Complications reported as having occurred by the longest follow-up time Seven trials report the proportion of individuals with this outcome. 22,23,35–39 The longest follow-up time is two weeks; the shortest is 48 hours. 36 Three of the seven trials report no events of complication in either trial arm. 35,36,38 In the comparison of topical anesthetics versus placebo or NSAID, topical anesthetics are associated with a higher proportion of complications in post-trauma participants at up to two weeks (RR, 1.13; 95% CI, 0.23 to 5.46; 3 RCTs; 242 participants; supplemental figure). For post-surgery participants at up to one week, the risk of complications also is higher with topical anesthetics (RR, 7.00; 95% CI, 0.38 to 128.02; 1 RCT; 44 participants; supplemental figure). 39 We also estimate risk differences (RDs) and find no evidence of differences in absolute risks for complications up to one week in both the post-surgery trials (RD, 0.03; 95% CI, -0.06 to 0.11; 3 RCTs; 119 participants; Fig. 4) 35–37 and post-trauma trials (RD, 0.00; 95% CI, -0.06 to 0.06; 4 RCTs; 275 participants; Fig. 4). 22,23,38,40 In one post-trauma trial, patients’ self-reported pain level is collected by telephone interview at the two-week mark. 40 In the single study comparing anesthetic plus NSAID versus placebo, proparacaine 0.05% plus diclofenac 0.1% versus placebo, the authors report no adverse events in either treatment arm up to one week post-surgery (RD, 0.00; 95% CI, -0.12 to 0.12; 30 participants). 35 For both comparisons, the certainty of evidence is very low because of potential risk of bias and imprecision. Important outcomes In the one study that reports treatment failure by 72 hours after treatment initiation, no oral analgesic use is used in either arm from 24 hours to 2 weeks. 40 The evidence of a difference between topical anesthetics and placebo is of very low certainty because of a potential risk of bias and imprecision. No study assesses quality of life. DISCUSSION Corneal abrasions from trauma or epithelial defects created during ophthalmic surgery occur commonly. In this review of nine RCTs in which a total of 556 participants with corneal abrasions are analyzed, we compare the safety and efficacy of topical ophthalmic anesthetic with or without NSAID versus placebo or NSAID. The evidence is of very low certainty for any difference between topical anesthetic and placebo in pain control, healing, or outcomes suggestive of anesthetic abuse. The main reasons for this level of certainty are small sample sizes and an overall high risk of bias. Use of anesthetic eye drops without close monitoring or attention to the amount dispensed (in one trial, 40 mL was prescribed for outpatient use) 38 creates a potential for significant ocular complications. Such sequelae may not be observed in trials with short follow-up or with high participant drop-out, characteristics of several trials in this review. Given the number of abrasions evaluated in emergency departments (EDs) each year, investigators should plan for larger sample sizes and a longer duration of follow-up, perhaps having a follow-up ophthalmic examination to confirm lack of recurrent erosion or contact lens-related keratitis. 1,41,42 These two conditions also present with disruption of the corneal epithelium but require ophthalmic care. Because most abrasions heal within a few days with just a topical antibiotic, high participant attrition in any such trial is anticipated, yet the dangers of anesthetic use increase with lack of monitoring, longer duration of use, higher concentration, or more frequent dosing than prescribed. 43,44 For a self-limited condition, the risk of blindness from corneal melt, infection, or perforation—all findings of topical anesthetic abuse—must be weighed against any possible benefit. The current review cannot address whether the numerous case reports of anesthetic complications describe outliers since most trials do not assess safety outcomes beyond one to two weeks. The case literature suggests certain patient populations may be at risk for topical anesthetic abuse. 4–21 These characteristics include a history of psychiatric illness, depression, dry eye, or drug abuse; certain occupations like manual labor that might prioritize return to work over close follow-up or recovery; or a medical or veterinary background that provides access to topical anesthetics. There are ethical concerns with enrolling participants at higher risk for anesthetic abuse. In any future trial, sample size assumptions (effect size, power) should be justified, and efficacy outcomes should include a more complete understanding and documentation of pain. Baseline and follow-up pain levels, function, and quality of life as well as complete demographic data would aid interpretation of applicability. Some trials record the baseline pain level in participants; others do not. A high proportion of participant drop-out is noted in one trial of post-traumatic abrasions. 23 This same trial employs a mixed-model approach for the multiple, repeated self-reported pain measurements from individuals that are “adjusted for pain on arrival, and allowing for individuals with different pain levels and pain reducing at different rates.” 23 No other included trial utilizes this method. Additionally, reliance on self-reported pain intensity following surgery can result in an overestimation of the needed intervention. 45,46 Lessons gained from the current opioid epidemic include the need for better understanding of pain, use of other treatment modalities, and focus on returning patients to normal function. 45,46 Given that topical anesthetic use also can be habit-forming, the same considerations may apply to pain control in corneal abrasion. A smaller systematic review of topical anesthetics for traumatic abrasions that includes 2 trials in this current review similarly concludes that topical anesthetic use is “currently not supported by evidence.” 47 One summary (not a systematic review) of interventions for post-PRK pain recommends against the long-term use of topical anesthetics. 48 Authors of another summary (not a systematic review) state topical anesthetics do not delay epithelial healing. 49 A third highlights the need for careful monitoring. 50 The small review 47 excludes a trial we had included, 34 and all three exclude two non-English language trials that we had included. 35,37 The American Academy of Ophthalmology’s 2022 Refractive Surgery Preferred Practice Pattern® states “small quantities of dilute topical anesthetic are sometimes used but warrant close supervision.” 51 Treatment guidelines and point-of-care resources generally cite case reports and series when recommending against the use of topical anesthetics for pain control. 43,44,52 In the United Kingdom, authors of the Clinical Knowledge Summary by National Institute for Health and Care Excellence (NICE) state that topical anesthetic can be used to aid examination but “repeat doses should be avoided as they can cause corneal epithelium toxicity and impair healing.” 53 A few years ago, the American Academy of Ophthalmology invited the American College of Emergency Physicians to issue joint guidelines regarding use of topical anesthetics for corneal abrasions because of concerns of potential harm. A joint working group from both organizations convened and reviewed the peer-reviewed literature. However, sidestepping concerns of the ophthalmologists regarding clinical recommendations, the emergency physicians of the group recently published guidelines without any ophthalmologist authors. 27 The guidelines endorse dispensing 1.5 to 2 mL topical anesthetics (q30 minutes for 24 hours) for corneal abrasions in the emergency department setting. 27 This amount (60–80 drops) actually would last 30–40 hours, although the guidelines state patients would be asked to discard drops after 24 hours. Guideline authors question the emphasis our Cochrane Systematic Review places on RCTs, question its relevance because it is “written solely” by ophthalmologists (not true), and claim an “existing practice pattern of ophthalmologists prescribing topical anesthetics for photorefractive keratectomy postoperative analgesia either for initial use or for breakthrough pain” (not accurate). Topical anesthetic use is exceedingly rare after PRK, and at least three papers the authors cite to support their use ironically describe complications or increased postoperative pain from anesthetic use. Only four trials in the current review report specific adverse events; most do not report events beyond one week. This short follow-up may lead to an inaccurately low estimate of adverse event rates. Topical anesthetic abuse is usually described in the literature at time points well beyond those of the trials in this review. In Turkey, where topical anesthetics were sold over the counter until 2012, one study found that median duration of use was 28 days (range, 10–112 days; 7 patients) before amniotic membrane transplantation was needed for corneal melt. 54 In a case series of patients with toxic keratopathy from topical anesthetic abuse, epithelial healing took a median of 17 days (range, 6–50 days; 19 patients). 21 The time from trauma to participant randomization is longer than for surgical participants by 24 to 36 hours. Post-trauma trials vary in whether patients with rust rings are included, which has implications for potential risk of bias and applicability of findings. Abrasion size in post-trauma trials likely varies as well, whereas the epithelial defect is more uniformly created in surgical procedures. Therefore, the baseline risk for slow epithelial healing and adverse events such as infection may differ systematically by setting. Because of different baseline risks, combining post-trauma and post-surgical subgroups when examining for complications does not make clinical sense and therefore is not done. In conclusion, there is insufficient evidence that topical anesthetics are more safe or effective than placebo for pain or healing of corneal abrasions of either surgical or traumatic origin. Trials with larger sample sizes, means to minimize attrition of trial participants, efficacy outcomes that reflect a better understanding and measurement of pain, and differentiation of abrasions (e.g., uncomplicated abrasions vs. ones with retained foreign material [or “rust rings”]) would reduce bias and increase certainty of evidence. Future trials and systematic reviews should include core outcome sets, comprised of multistakeholder consensus of measurable, reported standardized outcomes to improve consistency across studies and facilitate comparison of interventions. 55–59 Given that most abrasions are self-limited, trial participants should receive appropriate quantities of topical anesthetic to reduce the risk of complication and vision loss. Lessons learned from the opioid epidemic can apply to analgesia for corneal abrasion. Declarations Financial Support: LL, SL, and ICK all receive salary support from the Cochrane Eyes and Vision U.S. Project co-operative agreement with the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland (Grant Number: UG1EY020522). Conflicts of Interest: No other financial disclosures to report. Data Sharing Statement: This article is based on a published Cochrane Review. The data and data use policy can be found in the Cochrane Database of Systematic Reviews (CDSR) (see www.cochranelibrary.com for information). Cochrane Reviews are updated as new evidence emerges and in response to feedback; the CDSR should be consulted for the most recent version of the review. Author Contributions : I.C.K., S.L., and L.L. designed the study and extracted the data. L.L. analyzed the data. I.C.K. and S.L. interpreted the results of the analysis. S.L. and L.L. drafted the paper and I.C.K revised the manuscript. Competing Interests The authors declare no competing interests. References Channa R, Zafar SN, Canner JK, Haring RS, Schneider EB, Friedman DS. Epidemiology of Eye-Related Emergency Department Visits. JAMA Ophthalmol. Mar 2016;134(3):312–9. doi: 10.1001/jamaophthalmol.2015.5778 Vaziri K, Schwartz SG, Flynn HW, Jr., Kishor KS, Moshfeghi AA. Eye-related Emergency Department Visits in the United States, 2010. Ophthalmology. 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Jan 1 2023;49(1):30–34. doi: 10.1097/ICL.0000000000000956 Anderson-Quinones C, Zhu R, Tolley EA, Vestal R, Asbell P. Topical Anesthetics for Analgesia in Acute Corneal Abrasion: Eye Care Providers Survey. Eye Contact Lens. Apr 1 2023;49(4):143–146. doi: 10.1097/ICL.0000000000000971 Green SM, Tomaszewski C, Valente JH, Lo B, Milne K. Use of Topical Anesthetics in the Management of Patients With Simple Corneal Abrasions: Consensus Guidelines from the American College of Emergency Physicians. Ann Emerg Med. Feb 6 2024;doi: 10.1016/j.annemergmed.2024.01.004 Sulewski M, Leslie L, Liu SH, Ifantides C, Cho K, Kuo IC. Topical ophthalmic anesthetics for corneal abrasions. Cochrane Database Syst Rev. Aug 9 2023;8(8):CD015091. doi: 10.1002/14651858.CD015091.pub2 Higgins JPT, Savović J, Page MJ, Elbers RG, Sterne JAC. Chapter 8: Assessing risk of bias in a randomized trial. In: Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Schünemann HJ, Higgins JPT, Vist GE, Glasziou P, Akl EA, Skoetz N. Chapter 14: Completing ‘Summary of findings’ tables and grading the certainty of the evidence. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Higgins JPT, Li T, Deeks JJ. Chapter 6: Choosing effect measures and computing estimates of effect. In: Higgins J, Thomas J, Chandler J, Cumpston M, Li T, Page M, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions 6.3 (updated February 2022). Cochrane, 2022. McKenzie JE, Brennan SE, Ryan RE, Thomson HJ, Johnston RV. Chapter 9: Summarizing study characteristics and preparing for synthesis. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions version 6.3 (updated February 2022). Cochrane, 2022. Deeks JJ, Higgins JPT, Altman DG. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al, editor(s). Cochrane Handbook for Systematic Reviews of Interventions 6.3 (updated February 2022). Cochrane, 2022. Shahinian L, Jr., Jain S, Jager RD, Lin DT, Sanislo SS, Miller JF. Dilute topical proparacaine for pain relief after photorefractive keratectomy. Ophthalmology. Aug 1997;104(8):1327–32. doi: 10.1016/s0161-6420(97)30139-0 Lim HT, Kim YK, Tchah HW. [Efficacy of Topical NSAIDs and Anesthetic Drug in Reducing Post-PRK Pain: Comparative Study]. PRK 후 통증치료에 대한 점안 비스테로이드성 항염증약제들과 점안 마취제의 효과 비교. J Korean Ophthalmol Soc. 1999;40(1):61–9. Oksuz H, Tamer C. Pain relief after pterygium surgery with viscous lidocaine. Ophthalmologica . 2006 2006;220(5):323-6. doi: 10.1159/000094623 Montard M, Chopin C, Delbosc B, Muhieddine M. [Tetracaine versus diclofenac in the treatment of pain following refractive photokeratectomy]. Tétracaïne versus diclofénac dans le traitement de la douleur après photokératectomie réfractive. J Fr Ophtalmol. Feb 1999;22(1):14–20. Ball IM, Seabrook J, Desai N, Allen L, Anderson S. Dilute proparacaine for the management of acute corneal injuries in the emergency department. CJEM. Sep 2010;12(5):389–96. doi: 10.1017/s1481803500012537 Verma S, Corbett MC, Marshall J. A prospective, randomized, double-masked trial to evaluate the role of topical anesthetics in controlling pain after photorefractive keratectomy. Ophthalmology. Dec 1995;102(12):1918–24. doi: 10.1016/s0161-6420(95)30775-0 Ting JY, Barns KJ, Holmes JL. Management of Ocular Trauma in Emergency (MOTE) Trial: A pilot randomized double-blinded trial comparing topical amethocaine with saline in the outpatient management of corneal trauma. J Emerg Trauma Shock. Jan 2009;2(1):10–4. doi: 10.4103/0974-2700.44676 Nanji K, Gulamhusein H, Jindani Y, Hamilton D, Sabri K. Profile of eye-related emergency department visits in Ontario - a Canadian perspective. BMC Ophthalmol. Jul 10 2023;23(1):305. doi: 10.1186/s12886-023-02999-x Tang VD, Safi M, Mahavongtrakul A, et al. Ocular Anterior Segment Pathology in the Emergency Department: A 5-Year Study. Eye Contact Lens. Apr 1 2021;47(4):203–207. doi: 10.1097/ICL.0000000000000720 Ahmed F, House RJ, Feldman BH. Corneal Abrasions and Corneal Foreign Bodies. Prim Care. Sep 2015;42(3):363–75. doi: 10.1016/j.pop.2015.05.004 Wipperman JL, Dorsch JN. Evaluation and management of corneal abrasions. Am Fam Physician. Jan 15 2013;87(2):114–20. Pogatzki-Zahn E, Schnabel K, Kaiser U. Patient-reported outcome measures for acute and chronic pain: current knowledge and future directions. Curr Opin Anaesthesiol. Oct 2019;32(5):616–622. doi: 10.1097/ACO.0000000000000780 Sharfstein JM, Olsen Y. Lessons Learned From the Opioid Epidemic. JAMA . Sep 3 2019;322(9):809–810. doi: 10.1001/jama.2019.9794 Puls HA, Cabrera D, Murad MH, Erwin PJ, Bellolio MF. Safety and Effectiveness of Topical Anesthetics in Corneal Abrasions: Systematic Review and Meta-Analysis. J Emerg Med. Nov 2015;49(5):816–24. doi: 10.1016/j.jemermed.2015.02.051 Golan O, Randleman JB. Pain management after photorefractive keratectomy. Curr Opin Ophthalmol. Jul 2018;29(4):306–312. doi: 10.1097/ICU.0000000000000486 Garcia R, de Andrade DC, Teixeira MJ, Nozaki SS, Bechara SJ. Mechanisms of Corneal Pain and Implications for Postoperative Pain After Laser Correction of Refractive Errors. Clin J Pain. May 2016;32(5):450–8. doi: 10.1097/ajp.0000000000000271 Steigleman WA, Rose-Nussbaumer J, Al-Mohtaseb Z, et al. Management of Pain after Photorefractive Keratectomy: A Report by the American Academy of Ophthalmology. Ophthalmology. Jan 2023;130(1):87–98. doi: 10.1016/j.ophtha.2022.07.028 Jacobs DS, Lee JK, Shen TT, et al. Refractive Surgery Preferred Practice Pattern(R). Ophthalmology. Mar 2023;130(3):P61-P135. doi: 10.1016/j.ophtha.2022.10.032 College of Optometrists. Corneal abrasion Clinical Management Guidelines. Updated 7 June 2022. Accessed 16 July, 2023. https://www.college-optometrists.org/clinical-guidance/clinical-management-guidelines/cornealabrasion National Institute for Health and Care Excellence (NICE). Corneal superficial injury: Scenario: Management of corneal superficial injury. Updated June 2022. Accessed July 12, 2023. https://cks.nice.org.uk/topics/corneal-superficial-injury/management/management/ Burcu A, Dogan E, Yalniz-Akkaya Z, Ornek F. Early amniotic membrane transplantation for toxic keratopathy secondary to topical proparacaine abuse: a report of seven cases. Cutan Ocul Toxicol. Sep 2013;32(3):241–7. doi: 10.3109/15569527.2012.759959 McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain. Sep 2008;9(9):771–83. doi: 10.1016/j.jpain.2008.04.007 Boric K, Dosenovic S, Jelicic Kadic A, Boric M, Jeric M, Puljak L. Efficacy and Safety Outcomes in Systematic Reviews of Interventions for Postoperative Pain in Children: Comparison Against the Recommended Core Outcome Set. Pain Med. Nov 1 2018;19(11):2316–2321. doi: 10.1093/pm/pnx255 Wandner LD, Domenichiello AF, Beierlein J, et al. NIH's Helping to End Addiction Long-term(SM) Initiative (NIH HEAL Initiative) Clinical Pain Management Common Data Element Program. J Pain. Mar 2022;23(3):370–378. doi: 10.1016/j.jpain.2021.08.005 Wandner LD, Bloms-Funke P, Bova G, et al. INTEGRATE-Pain: a transatlantic consortium to advance development of effective pain management. Pain Med. Jun 1 2023;24(6):730–733. doi: 10.1093/pm/pnad033 Gewandter JS, Smith SM, Dworkin RH, et al. Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations. Pain. Nov 1 2021;162(11):2669–2681. doi: 10.1097/j.pain.0000000000002283 Additional Declarations There is NO Competing Interest. Supplementary Files SuppFig1.pdf Supplemental figure. Forest plot showing estimated risk ratios (RR) with their 95% CI, for complications. The proportion of post-trauma participants with complications up to one week and post-surgical participants with complications up to two weeks was higher with topical anesthetics than with placebo. CI = confidence interval; M-H = Mantel-Haenszel. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4160700","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":303607350,"identity":"88b70903-7630-4fb7-861c-17d8122215e3","order_by":0,"name":"Irene Kuo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArUlEQVRIiWNgGAWjYBACNiBkYKhgS2BgBtI8xGs5Q4oWkCYGxjaGBDCbKC187MfSJD7O48vTbWdgfPC2jRg7eNKOSc7cxlZsdpiB2XAuUVok2NukebexJW47zMAmzUu8ljlgLey/idTCdkyatwFiCzNxWnjSki1nHANpYWyWnHOOCC3y7ccMb3yoOZa47fzhgx/elBGhBQqOATFjA/HqgaCGJNWjYBSMglEwwgAAX7UuqZbvnrkAAAAASUVORK5CYII=","orcid":"","institution":"Wilmer Eye Institute Johns Hopkins University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Irene","middleName":"","lastName":"Kuo","suffix":""},{"id":303607351,"identity":"83d0fe81-2857-4b77-8a08-07ab67684ff7","order_by":1,"name":"Louis Leslie","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Louis","middleName":"","lastName":"Leslie","suffix":""},{"id":303607352,"identity":"55aad26b-624e-487c-af7b-8b7d1ed948cd","order_by":2,"name":"Su-Hsun Liu","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Su-Hsun","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-03-25 04:45:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4160700/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4160700/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-025-00979-4","type":"published","date":"2025-09-24T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57705471,"identity":"51cfeda4-8db8-4ebd-a256-647fbed2b1bb","added_by":"auto","created_at":"2024-06-04 14:50:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":613418,"visible":true,"origin":"","legend":"\u003cp\u003ePreferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram showing identification and selection of randomized controlled trials that compare different topical anesthetics with or without co-interventions to placebo or active control for corneal abrasions.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/afb3bbd9cf2f90747916b2d3.png"},{"id":57706502,"identity":"2b4a1be4-db89-4553-89b9-5cee0078d84f","added_by":"auto","created_at":"2024-06-04 14:58:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":188295,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing mean differences with their 95% confidence intervals (CI) for self-reported pain at 24 hours. Compared with placebo, topical anesthetics are associated with a moderate reduction in self-reported pain at 24 hours in post-surgical trials but show little or no difference in effect in post-trauma participants. However, compared with NSAIDs in post-surgical participants, self-reported pain is increased in the topical anesthetic group compared with the NSAID group.\u003cbr\u003e\n CI = confidence interval; IV = Inverse Variance; SD = standard deviation; VAS = visual analog scale.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/b42912368d4fef103579fc34.png"},{"id":57706503,"identity":"75be424a-ce5d-4007-9895-9dde860c1d49","added_by":"auto","created_at":"2024-06-04 14:58:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":128285,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing estimated risk ratios (RR) with their 95% CI, for proportions of participants with persistent epithelial defects. The proportion of post-trauma participants with persistent \u0026nbsp;epithelial defects is higher with topical anesthetics than with placebo or NSAID. However, in post-surgical participants, the proportion of unresolved epithelial defects is higher with placebo than with topical anesthetics. CI = confidence interval; M-H = Mantel-Haenszel.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/38085f724246052c8f1e9bf0.png"},{"id":57705469,"identity":"71a25922-6503-4ee9-9481-cc17aef85d6c","added_by":"auto","created_at":"2024-06-04 14:50:30","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":223685,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot showing estimated risk difference with 95% CI, for complications. There is no evidence of a difference in absolute risk with topical anesthetic use versus placebo or NSAID. CI = confidence interval; M-H = Mantel-Haenszel.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/d8d72dfedf86bbd293702305.png"},{"id":92146661,"identity":"0d0bfb2c-48af-4f8a-823d-c1c4b8ed6eb8","added_by":"auto","created_at":"2025-09-25 07:15:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1658932,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/15bfef41-e46b-4096-9f62-e630afa76708.pdf"},{"id":57705468,"identity":"3bcadfd7-ddc0-49b6-a41b-8d38009bb5c3","added_by":"auto","created_at":"2024-06-04 14:50:30","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":157687,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental figure. Forest plot showing estimated risk ratios (RR) with their 95% CI, for complications. The proportion of post-trauma participants with complications up to one week and post-surgical participants with complications up to two weeks was higher with topical anesthetics than with placebo. CI = confidence interval; M-H = Mantel-Haenszel.\u003c/p\u003e","description":"","filename":"SuppFig1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4160700/v1/f2055452e4d7d351fd1cd29d.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Topical Ophthalmic Anesthetics for Corneal Abrasions: Findings from a Cochrane Systematic Review and Meta-Analysis","fulltext":[{"header":"PLAIN LANGUAGE SUMMARY ","content":"\u003cp\u003eThe cornea, the clear, dome-shaped structure covering the iris, is one of the most pain-sensitive tissues in the body. Traumatic abrasions (disruption of the epithelium, the top corneal layer) account for \u0026gt; 10% of all eye-related visits to emergency rooms in the US. Epithelial removal also occurs in some eye surgeries. Topical anesthetic drops for corneal abrasions are controversial; they can be habit-forming and can cause corneal scar or blindness. Nonetheless, a growing number of emergency department providers prescribes these drops for corneal abrasions, despite the fact most heal within days. By carefully analyzing 9 randomized controlled trials, we do not find enough evidence that topical anesthetics reduce pain, improve healing, or decrease the chance of complication compared with placebo. \u0026nbsp;\u003c/p\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003eCorneal abrasions, loss of the corneal epithelium, can occur from trauma, ocular surgery, dryness, and exposure. They account for 13% of eye-related emergency department visits in the US, with an annual incidence of 3 per 1000 persons and a higher male prevalence.\u003csup\u003e1\u0026ndash;3\u003c/sup\u003e Traumatic abrasions present with symptoms like pain, photophobia, redness, and tearing. As the cornea is one of the most highly innervated tissues in the body, corneal nociceptors, especially mechanoreceptors, contribute to intense eye pain until healing occurs. Although most small to medium-sized corneal abrasions heal within a few days, complications like corneal erosions and infection may require medical or surgical intervention. In contrast, post-surgical corneal epithelial defects benefit from a sterile field and controlled wound construction.\u003c/p\u003e \u003cp\u003eIn medicine, topical nonsteroidal anti-inflammatory drugs (NSAIDs) and anesthetic drugs are used for localized analgesia with limited systemic effects. However, numerous case reports describe ophthalmic complications from use of high concentrations of topical anesthetics, at excessive frequency, or for prolonged periods of time, including corneal infiltrate, stromal keratolysis (\u0026ldquo;melt\u0026rdquo;), endothelial injury, and perforation\u003csup\u003e4\u0026ndash;21\u003c/sup\u003e \u0026ndash; all of which can lead to vision loss. Recent emergency department studies have deemed outpatient use of prescribed topical anesthetics as safe and effective for corneal abrasions.\u003csup\u003e22\u0026ndash;24\u003c/sup\u003e This assessment contrasts with the experience of ophthalmologists,\u003csup\u003e6\u0026ndash;23\u003c/sup\u003e leading to renewed questions about outpatient anesthetic use. The lack of consensus guidelines may account for variations in practice within and across specialties.\u003csup\u003e25\u0026ndash;27\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe main objective of this summary of our Cochrane systematic review is to report the comparative effectiveness and safety of topical ophthalmic anesthetics compared with placebo or other treatments for corneal abrasions of any etiology, based on the best available evidence.\u003csup\u003e28\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn nine eligible randomized controlled trials (RCTs) describing 556 participants with corneal abrasions from traumatic or surgical origin, we find insufficient evidence to support outpatient use of topical ophthalmic anesthetics compared with placebo for reducing pain, improving re-epithelialization, or reducing complication risk in corneal abrasions.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003cem\u003eEligibility criteria for studies and outcomes of interest\u003c/em\u003e:\u003c/h2\u003e \u003cp\u003eWe examined only randomized controlled trials (RCTs). Eligible trials compare topical ophthalmic anesthetics (amide or ester class) with a control group (placebo, non-treatment, or alternative treatment). Trials in which topical anesthetics with an NSAID were compared with a control group were eligible. We considered trials that enrolled participants of all ages with corneal abrasions within 48 hours of presentation from accidental trauma or ophthalmic surgery.\u003c/p\u003e \u003cp\u003eThe primary review outcomes were (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) mean reduction in self-reported pain on a visual analog scale (VAS), where smaller numbers represent less pain, at 24, 48, and 72 hours after treatment initiation; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) the proportion of participants without complete resolution of epithelial defects by 24\u0026ndash;72 hours; and 3) the proportion of participants with adverse events (e.g. microbial keratitis or stromal infiltration, corneal stromal thinning, corneal perforation, surgical interventions) reported at the longest follow-up time of the study. For secondary outcomes, we considered treatment failure (the proportion of participants who required rescue oral analgesics by 72 hours after treatment initiation) and quality of life assessed by a validated instrument at the longest follow-up time of the study. Trials were not excluded on the basis of outcome reporting.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e\u003cem\u003eSearch methods for identifying studies\u003c/em\u003e:\u003c/h2\u003e \u003cp\u003eWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase.com, ClinicalTrials.gov (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.cochranelibrary.com\" target=\"_blank\"\u003ewww.clinicaltrials.gov\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.clinicaltrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), and the WHO International Clinical Trials Registry Platform (ICTRP) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.cochranelibrary.com\" target=\"_blank\"\u003ewww.who.int/ictrp/search/en\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.who.int/ictrp/search/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) to identify potentially eligible RCTs for this review. We did not impose restrictions on the search date or language of publication. The last date of search was February 10, 2023.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection:\u003c/h2\u003e \u003cp\u003ePairs of review authors worked independently to review titles and abstracts as well as full-text records against the eligibility criteria; disagreements were resolved by discussion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData collection and risk of bias:\u003c/h2\u003e \u003cp\u003eAuthors independently extracted the following data from included studies: trial characteristics, methods, participants, interventions, outcomes, and source of funding. Two review authors independently applied the Cochrane's Risk of Bias version 2 (RoB2) tool\u003csup\u003e29\u003c/sup\u003e to assess risk of bias in the efficacy outcome (pain control by 48 hours) and the safety outcome (complications at the longest follow-up time). We judged each study that reported either outcome to have been at \u0026ldquo;low risk,\u0026rdquo; \u0026ldquo;high risk\u0026rdquo; or raising some concerns for risk of bias. An overall Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment of the certainty level of evidence was performed based on four main criteria: risk of bias, inconsistency, indirectness, and imprecision.\u003csup\u003e30\u003c/sup\u003e Disagreements were resolved by discussion within the author team.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eData analysis and synthesis:\u003c/h2\u003e \u003cp\u003eFor the continuous outcome of pain assessment, we estimated the difference in means (\u0026ldquo;mean difference\u0026rdquo;) (MD) with 95% confidence intervals (CI). For dichotomous outcomes, we estimated the risk ratios (RR) with 95% CI. We estimated the risk difference (RD) with 95% CI for trials reporting no events in either treatment group.\u003csup\u003e31\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eTo determine whether results could be combined in meta-analyses, we assessed the trials for clinical and methodological heterogeneity in trial design, eligibility of trial participants, intervention and comparator differences, and outcome definitions.\u003csup\u003e32,33\u003c/sup\u003e We evaluated the amount of statistical heterogeneity using the I\u003csup\u003e2\u003c/sup\u003e statistic outlined in the Cochrane Handbook.\u003csup\u003e33\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eWe present analysis of nine RCTs (21 study reports) after a literature search yielded 7641 unique titles and abstracts that were screened, of which we reviewed 39 potentially relevant full-text publications (Fig.\u0026nbsp;1). Our quantitative analysis includes 8 of the 9 RCTs. One trial does not report data in a manner amenable to analysis for our specified outcomes.\u003csup\u003e34\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAll included trials are parallel-group, 2-arm RCTs, except for one 7-arm trial.\u003csup\u003e35\u003c/sup\u003e The trials span across eight countries from 1994 to 2021. The four post-traumatic abrasion trials were conducted in emergency departments. Four trials did not receive industry funding; funding information is unknown for five trials.\u003csup\u003e34\u0026ndash;38\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe included trials report data from 626 eligible participants who were randomized. After selecting the appropriate 3 arms from a 7-arm trial,\u003csup\u003e35\u003c/sup\u003e we analyzed 556 participants with a median of 45 participants per trial (interquartile range [IQR], 44\u0026ndash;74; 9 RCTs). A higher proportion of women are enrolled in surgical trials (60%; 166/278 participants; 4 RCTs) than in post-trauma settings (21%; 65/314 participants; 4 RCTs).\u003c/p\u003e \u003cp\u003eThe following topical anesthetics are compared with placebo (Table\u0026nbsp;1): tetracaine 1% (2 RCTs),\u003csup\u003e23,39\u003c/sup\u003e 0.5% (1 RCT),\u003csup\u003e22\u003c/sup\u003e and 0.4% (1 RCT);\u003csup\u003e40\u003c/sup\u003e proparacaine 0.05% (3 RCTs);\u003csup\u003e34,35,38\u003c/sup\u003e and lidocaine 2% (1 RCT).\u003csup\u003e36\u003c/sup\u003e One multi-arm trial compares proparacaine 0.05% and proparacaine 0.05% with topical diclofenac 0.1% against placebo. \u003csup\u003e35\u003c/sup\u003e One trial has an NSAID active control (diclofenac 0.1%).\u003csup\u003e37\u003c/sup\u003e When reported, the total amount of topical anesthetic dispensed by emergency departments ranges from 1.5 mL to 40 mL (approximately 30\u0026ndash;800 drops).\u003c/p\u003e \u003cp\u003eFour studies analyze abrasions of traumatic etiology in 314 participants (314 eyes).\u003csup\u003e22,23,38,40\u003c/sup\u003e Most abrasions involve corneal foreign bodies (47%; 148 eyes) or direct trauma (19%; 61 eyes). Five studies describe 242 participants (256 eyes) with post-surgical corneal defects, four from photorefractive keratectomy (PRK)\u003csup\u003e34,35,37,39\u003c/sup\u003e and one from pterygium surgery.\u003csup\u003e36\u003c/sup\u003e Overall, the median study length is 7 days (IQR, 7\u0026ndash;14 days) with a median of 11 days (IQR, 7\u0026ndash;18 days) for post-trauma trials and 7 days (IQR, 3\u0026ndash;7 days) for post-surgical trials. Overall, the median treatment duration is 24 hours (IQR, 24\u0026ndash;168 hours) with a median of 36 hours (IQR, 24\u0026ndash;78 hours) for post-trauma trials and 24 hours (IQR, 24\u0026ndash;168 hours) for post-surgical trials.\u003c/p\u003e \u003cp\u003eTwo (67%) of the three trials describing ocular pain results have an overall high risk of bias. Five (71%) of the seven trials describing ocular complications have an overall high risk of bias, primarily from missing outcome data and selective reporting of results.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEffectiveness and safety of interventions\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eCritical outcomes\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section4\"\u003e \u003ch2\u003ePain control from baseline to 24 hours after treatment initiation\u003c/h2\u003e \u003cp\u003eThe combined estimate for pain scores reported by post-surgical participants\u003csup\u003e35,36,39\u003c/sup\u003e suggests that when compared with placebo, topical anesthetics reduce pain by 1.28 on a 10-point VAS (MD, -1.28; 95% CI, -1.76 to -0.80; 3 RCTs; 119 participants; Fig.\u0026nbsp;2). In contrast, one post-PRK trial reports 0.82 higher pain scores on a 10-point VAS with tetracaine compared with NSAID (MD, 0.82; 95% CI, 0.01 to 1.63; 74 participants; Fig.\u0026nbsp;2).\u003csup\u003e37\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eNo evidence of a difference in pain control (MD, -0.04; 95% CI, -0.10 to 0.02) is found in a trial using a mixed-model to account for multiple measurements, to which 76 (62%) of 122 of post-trauma participants contributed data.\u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne post-surgical trial compares an anesthetic plus an NSAID with placebo.\u003csup\u003e35\u003c/sup\u003e The estimated difference in means in reduction in pain scores (i.e., the \u0026ldquo;mean difference\u0026rdquo; or MD) from this study indicates anesthetic plus NSAID reduces pain scores at 24 hours when compared with placebo (MD, -5.72 on a 10-point scale; 95% CI, -7.35\u0026ndash;-4.09; 30 participants).\u003c/p\u003e \u003cp\u003eThe certainty of evidence for all effect estimates is very low because of potential risk of bias and imprecision.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePain control from baseline to 48 hours after treatment initiation\u003c/h2\u003e \u003cp\u003eUsing a 10-point VAS, post-surgical participants of one trial report little pain control relative to placebo (MD, 0.41; 95% CI, -0.45 to 1.27; 44 participants.\u003csup\u003e39\u003c/sup\u003e Post-trauma participants in one trial report 5.68 lower pain scores with tetracaine 0.5% than placebo (MD, -5.68; 95% CI, -6.38 to -4.98; 111 participants).\u003csup\u003e22\u003c/sup\u003e One post-trauma trial is excluded from this analysis because 57% of 124 randomized participants are lost to follow up.\u003csup\u003e23\u003c/sup\u003e The overall certainty of evidence is very low because of a high risk of bias, imprecision, and inconsistency across studies.\u003c/p\u003e \u003cp\u003eNo trial records pain control from baseline to 72 hours after treatment initiation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEpithelial healing by 24 to 72 hours\u003c/h2\u003e \u003cp\u003eIn three post-trauma trials\u003csup\u003e22,23,40\u003c/sup\u003e the risk of persistent epithelial defects assessed at 24 to 72 hours is 37% higher with varying concentrations of tetracaine compared with placebo (RR, 1.37; 95% CI, 0.78 to 2.42; 3 RCTs; 221 participants; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;3). However, a decrease in the proportion of participants with persistent defects is found in a trial of 30 post-surgical participants using proparacaine 0.05% (RR, 0.14; 95% CI, 0.01 to 2.55; Fig.\u0026nbsp;3) and proparacaine 0.05% plus diclofenac 0.1% (RR, 0.33; 95% CI, 0.04 to 2.85), compared with placebo.\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOverall, there is no evidence of differences although the evidence is of very low certainty because of a high risk of bias, inconsistency, and imprecision.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eComplications reported as having occurred by the longest follow-up time\u003c/h2\u003e \u003cp\u003eSeven trials report the proportion of individuals with this outcome.\u003csup\u003e22,23,35\u0026ndash;39\u003c/sup\u003e The longest follow-up time is two weeks; the shortest is 48 hours.\u003csup\u003e36\u003c/sup\u003e Three of the seven trials report no events of complication in either trial arm.\u003csup\u003e35,36,38\u003c/sup\u003e In the comparison of topical anesthetics versus placebo or NSAID, topical anesthetics are associated with a higher proportion of complications in post-trauma participants at up to two weeks (RR, 1.13; 95% CI, 0.23 to 5.46; 3 RCTs; 242 participants; supplemental figure). For post-surgery participants at up to one week, the risk of complications also is higher with topical anesthetics (RR, 7.00; 95% CI, 0.38 to 128.02; 1 RCT; 44 participants; supplemental figure).\u003csup\u003e39\u003c/sup\u003e We also estimate risk differences (RDs) and find no evidence of differences in absolute risks for complications up to one week in both the post-surgery trials (RD, 0.03; 95% CI, -0.06 to 0.11; 3 RCTs; 119 participants; Fig.\u0026nbsp;4)\u003csup\u003e35\u0026ndash;37\u003c/sup\u003e and post-trauma trials (RD, 0.00; 95% CI, -0.06 to 0.06; 4 RCTs; 275 participants; Fig.\u0026nbsp;4).\u003csup\u003e22,23,38,40\u003c/sup\u003e In one post-trauma trial, patients\u0026rsquo; self-reported pain level is collected by telephone interview at the two-week mark.\u003csup\u003e40\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn the single study comparing anesthetic plus NSAID versus placebo, proparacaine 0.05% plus diclofenac 0.1% versus placebo, the authors report no adverse events in either treatment arm up to one week post-surgery (RD, 0.00; 95% CI, -0.12 to 0.12; 30 participants).\u003csup\u003e35\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFor both comparisons, the certainty of evidence is very low because of potential risk of bias and imprecision.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eImportant outcomes\u003c/h2\u003e \u003cp\u003eIn the one study that reports treatment failure by 72 hours after treatment initiation, no oral analgesic use is used in either arm from 24 hours to 2 weeks.\u003csup\u003e40\u003c/sup\u003e The evidence of a difference between topical anesthetics and placebo is of very low certainty because of a potential risk of bias and imprecision. No study assesses quality of life.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eCorneal abrasions from trauma or epithelial defects created during ophthalmic surgery occur commonly. In this review of nine RCTs in which a total of 556 participants with corneal abrasions are analyzed, we compare the safety and efficacy of topical ophthalmic anesthetic with or without NSAID versus placebo or NSAID. The evidence is of very low certainty for any difference between topical anesthetic and placebo in pain control, healing, or outcomes suggestive of anesthetic abuse. The main reasons for this level of certainty are small sample sizes and an overall high risk of bias. Use of anesthetic eye drops without close monitoring or attention to the amount dispensed (in one trial, 40 mL was prescribed for outpatient use)\u003csup\u003e38\u003c/sup\u003e creates a potential for significant ocular complications. Such sequelae may not be observed in trials with short follow-up or with high participant drop-out, characteristics of several trials in this review.\u003c/p\u003e \u003cp\u003eGiven the number of abrasions evaluated in emergency departments (EDs) each year, investigators should plan for larger sample sizes and a longer duration of follow-up, perhaps having a follow-up ophthalmic examination to confirm lack of recurrent erosion or contact lens-related keratitis.\u003csup\u003e1,41,42\u003c/sup\u003e These two conditions also present with disruption of the corneal epithelium but require ophthalmic care. Because most abrasions heal within a few days with just a topical antibiotic, high participant attrition in any such trial is anticipated, yet the dangers of anesthetic use increase with lack of monitoring, longer duration of use, higher concentration, or more frequent dosing than prescribed.\u003csup\u003e43,44\u003c/sup\u003e For a self-limited condition, the risk of blindness from corneal melt, infection, or perforation\u0026mdash;all findings of topical anesthetic abuse\u0026mdash;must be weighed against any possible benefit.\u003c/p\u003e \u003cp\u003eThe current review cannot address whether the numerous case reports of anesthetic complications describe outliers since most trials do not assess safety outcomes beyond one to two weeks. The case literature suggests certain patient populations may be at risk for topical anesthetic abuse.\u003csup\u003e4\u0026ndash;21\u003c/sup\u003e These characteristics include a history of psychiatric illness, depression, dry eye, or drug abuse; certain occupations like manual labor that might prioritize return to work over close follow-up or recovery; or a medical or veterinary background that provides access to topical anesthetics. There are ethical concerns with enrolling participants at higher risk for anesthetic abuse.\u003c/p\u003e \u003cp\u003eIn any future trial, sample size assumptions (effect size, power) should be justified, and efficacy outcomes should include a more complete understanding and documentation of pain. Baseline and follow-up pain levels, function, and quality of life as well as complete demographic data would aid interpretation of applicability. Some trials record the baseline pain level in participants; others do not. A high proportion of participant drop-out is noted in one trial of post-traumatic abrasions.\u003csup\u003e23\u003c/sup\u003e This same trial employs a mixed-model approach for the multiple, repeated self-reported pain measurements from individuals that are \u0026ldquo;adjusted for pain on arrival, and allowing for individuals with different pain levels and pain reducing at different rates.\u0026rdquo;\u003csup\u003e23\u003c/sup\u003e No other included trial utilizes this method. Additionally, reliance on self-reported pain intensity following surgery can result in an overestimation of the needed intervention.\u003csup\u003e45,46\u003c/sup\u003e Lessons gained from the current opioid epidemic include the need for better understanding of pain, use of other treatment modalities, and focus on returning patients to normal function.\u003csup\u003e45,46\u003c/sup\u003e Given that topical anesthetic use also can be habit-forming, the same considerations may apply to pain control in corneal abrasion.\u003c/p\u003e \u003cp\u003eA smaller systematic review of topical anesthetics for traumatic abrasions that includes 2 trials in this current review similarly concludes that topical anesthetic use is \u0026ldquo;currently not supported by evidence.\u0026rdquo;\u003csup\u003e47\u003c/sup\u003e One summary (not a systematic review) of interventions for post-PRK pain recommends against the long-term use of topical anesthetics.\u003csup\u003e48\u003c/sup\u003e Authors of another summary (not a systematic review) state topical anesthetics do not delay epithelial healing.\u003csup\u003e49\u003c/sup\u003e A third highlights the need for careful monitoring.\u003csup\u003e50\u003c/sup\u003e The small review\u003csup\u003e47\u003c/sup\u003e excludes a trial we had included,\u003csup\u003e34\u003c/sup\u003e and all three exclude two non-English language trials that we had included.\u003csup\u003e35,37\u003c/sup\u003e The American Academy of Ophthalmology\u0026rsquo;s 2022 Refractive Surgery Preferred Practice Pattern\u0026reg; states \u0026ldquo;small quantities of dilute topical anesthetic are sometimes used but warrant close supervision.\u0026rdquo;\u003csup\u003e51\u003c/sup\u003e Treatment guidelines and point-of-care resources generally cite case reports and series when recommending against the use of topical anesthetics for pain control.\u003csup\u003e43,44,52\u003c/sup\u003e In the United Kingdom, authors of the Clinical Knowledge Summary by National Institute for Health and Care Excellence (NICE) state that topical anesthetic can be used to aid examination but \u0026ldquo;repeat doses should be avoided as they can cause corneal epithelium toxicity and impair healing.\u0026rdquo;\u003csup\u003e53\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e A few years ago, the American Academy of Ophthalmology invited the American College of Emergency Physicians to issue joint guidelines regarding use of topical anesthetics for corneal abrasions because of concerns of potential harm. A joint working group from both organizations convened and reviewed the peer-reviewed literature. However, sidestepping concerns of the ophthalmologists regarding clinical recommendations, the emergency physicians of the group recently published guidelines without any ophthalmologist authors.\u003csup\u003e27\u003c/sup\u003e The guidelines endorse dispensing 1.5 to 2 mL topical anesthetics (q30 minutes for 24 hours) for corneal abrasions in the emergency department setting.\u003csup\u003e27\u003c/sup\u003e This amount (60\u0026ndash;80 drops) actually would last 30\u0026ndash;40 hours, although the guidelines state patients would be asked to discard drops after 24 hours. Guideline authors question the emphasis our Cochrane Systematic Review places on RCTs, question its relevance because it is \u0026ldquo;written solely\u0026rdquo; by ophthalmologists (not true), and claim an \u0026ldquo;existing practice pattern of ophthalmologists prescribing topical anesthetics for photorefractive keratectomy postoperative analgesia either for initial use or for breakthrough pain\u0026rdquo; (not accurate). Topical anesthetic use is exceedingly rare after PRK, and at least three papers the authors cite to support their use ironically describe complications or increased postoperative pain from anesthetic use.\u003c/p\u003e \u003cp\u003eOnly four trials in the current review report specific adverse events; most do not report events beyond one week. This short follow-up may lead to an inaccurately low estimate of adverse event rates. Topical anesthetic abuse is usually described in the literature at time points well beyond those of the trials in this review. In Turkey, where topical anesthetics were sold over the counter until 2012, one study found that median duration of use was 28 days (range, 10\u0026ndash;112 days; 7 patients) before amniotic membrane transplantation was needed for corneal melt.\u003csup\u003e54\u003c/sup\u003e In a case series of patients with toxic keratopathy from topical anesthetic abuse, epithelial healing took a median of 17 days (range, 6\u0026ndash;50 days; 19 patients).\u003csup\u003e21\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe time from trauma to participant randomization is longer than for surgical participants by 24 to 36 hours. Post-trauma trials vary in whether patients with rust rings are included, which has implications for potential risk of bias and applicability of findings. Abrasion size in post-trauma trials likely varies as well, whereas the epithelial defect is more uniformly created in surgical procedures. Therefore, the baseline risk for slow epithelial healing and adverse events such as infection may differ systematically by setting. Because of different baseline risks, combining post-trauma and post-surgical subgroups when examining for complications does not make clinical sense and therefore is not done.\u003c/p\u003e \u003cp\u003eIn conclusion, there is insufficient evidence that topical anesthetics are more safe or effective than placebo for pain or healing of corneal abrasions of either surgical or traumatic origin. Trials with larger sample sizes, means to minimize attrition of trial participants, efficacy outcomes that reflect a better understanding and measurement of pain, and differentiation of abrasions (e.g., uncomplicated abrasions vs. ones with retained foreign material [or \u0026ldquo;rust rings\u0026rdquo;]) would reduce bias and increase certainty of evidence. Future trials and systematic reviews should include core outcome sets, comprised of multistakeholder consensus of measurable, reported standardized outcomes to improve consistency across studies and facilitate comparison of interventions.\u003csup\u003e55\u0026ndash;59\u003c/sup\u003e Given that most abrasions are self-limited, trial participants should receive appropriate quantities of topical anesthetic to reduce the risk of complication and vision loss. Lessons learned from the opioid epidemic can apply to analgesia for corneal abrasion.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial Support:\u003c/strong\u003e LL, SL, and ICK all receive salary support from the Cochrane Eyes and Vision U.S. Project co-operative agreement with the National Eye Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland (Grant Number: UG1EY020522).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u003c/strong\u003e No other financial disclosures to report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement:\u0026nbsp;\u003c/strong\u003eThis article is based on a published Cochrane Review. The data and data use policy can be found in the Cochrane Database of Systematic Reviews (CDSR) (see www.cochranelibrary.com for information). Cochrane Reviews are updated as new evidence emerges and in response to feedback; the CDSR should be consulted for the most recent version of the review.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eI.C.K., S.L., and L.L. designed the study and extracted the data. L.L. analyzed the data. I.C.K. and S.L. interpreted the results of the analysis. S.L. and L.L. drafted the paper and I.C.K revised the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChanna R, Zafar SN, Canner JK, Haring RS, Schneider EB, Friedman DS. Epidemiology of Eye-Related Emergency Department Visits. JAMA Ophthalmol. 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Nov 1 2021;162(11):2669\u0026ndash;2681. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/j.pain.0000000000002283\u003c/span\u003e\u003cspan address=\"10.1097/j.pain.0000000000002283\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"corneal injuries, corneal abrasion, eye pain, local anesthetics, corneal epithelium, emergency room visits","lastPublishedDoi":"10.21203/rs.3.rs-4160700/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4160700/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eDespite potential benefit, outpatient use of topical ophthalmic anesthetics can result in poor healing, infection, scar, and blindness. An unbiased analysis of randomized controlled trials (RCTs) is needed to examine their effectiveness and safety compared with placebo or other treatments for corneal abrasions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCochrane Central Register of Controlled Trials, MEDLINE, Embase.com, Latin American and Caribbean Health Sciences, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched on February 10, 2023, without restriction on language or publication date.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eSystematic review and meta-analysis of nine RCTs describing 314 participants with post-traumatic abrasions and 242 participants with post-surgical abrasions, with a median study length of 7 days (interquartile range, 7\u0026ndash;14), show no evidence of a difference in pain control between anesthetics and placebo at 24 hours in post-trauma cases. Self-reported pain at 24 hours is reduced with anesthetics plus topical nonsteroid anti-inflammatory drug in post-surgical participants (mean difference [MD], -5.72 on a 10-point scale; 95% CI, -7.35 to -4.09; 1 RCT; 30 participants) and at 48 hours with anesthetics alone in post-trauma participants (MD, -5.68; 95% CI, -6.38 to -4.98; 1 RCT; 111 participants). Anesthetics are associated with 37% increased risk of non-healing defects (risk ratio, 1.37; 95% CI, 0.78 to 2.42; 3 RCTs; 221 post-trauma participants). All evidence is of very low certainty. Over 50% of trials have an overall high risk of bias.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAvailable evidence is insufficient to support outpatient use of topical anesthetics for corneal abrasions with respect to pain, re-epithelialization, and complication risk.\u003c/p\u003e","manuscriptTitle":"Topical Ophthalmic Anesthetics for Corneal Abrasions: Findings from a Cochrane Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-04 14:50:26","doi":"10.21203/rs.3.rs-4160700/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"198a0fea-e384-48d9-8389-dc5c27a0c33f","owner":[],"postedDate":"June 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32050387,"name":"Health sciences/Signs and symptoms"},{"id":32050388,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-09-25T07:14:56+00:00","versionOfRecord":{"articleIdentity":"rs-4160700","link":"https://doi.org/10.1038/s43856-025-00979-4","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2025-09-24 04:00:00","publishedOnDateReadable":"September 24th, 2025"},"versionCreatedAt":"2024-06-04 14:50:26","video":"","vorDoi":"10.1038/s43856-025-00979-4","vorDoiUrl":"https://doi.org/10.1038/s43856-025-00979-4","workflowStages":[]},"version":"v1","identity":"rs-4160700","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4160700","identity":"rs-4160700","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}