Topical ophthalmic anesthetics for corneal abrasions

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effectiveness and safety of topical ophthalmic anesthetics compared to placebo or other treatments in persons with corneal abrasions.

Background

Description of the condition

Corneal abrasions (also known as corneal epithelial defects) are distinct losses of the corneal epithelium, the superficial, regenerative, squamous epithelial barrier of the cornea (Nishida 2022). Etiologies of abrasions include accidental trauma (mechanical, chemical, or phototoxic), ocular surgery, corneal dryness, exposure (inadequate eyelid coverage of the cornea), neurotrophic disease, ocular inflammation, infection, as well as a variety of other intrinsic ocular pathologies (Nishida 2022). Corneal abrasions are a common emergency, representing about 13% of eye‐related emergency room visits in the United States (Channa 2016; Vaziri 2016) with an estimated annual incidence of 3 per 1000 persons and a roughly two‐to‐one male predominance according to the National Ambulatory Medical Care Survey (NAMCS) (McGwin 2005). Globally there are an estimated 55 million eye injuries each year with 750,000 requiring hospitalization (Négrel 1998).

Abrasions resulting from trauma may inoculate the eye with foreign matter and microbial organisms, leading to corneal infection. Symptoms of a corneal abrasion include intense pain, photophobia, redness, and tearing. Depending on the healthcare setting, corneal abrasions may be diagnosed and initially treated by general practitioners, emergency medicine providers, or eye care specialists (Ahmed 2015). On exam, corneal epithelial defects are best visualized by instilling fluorescein dye into the tear film, which adheres to bare stroma (but not intact epithelium), and will fluoresce green when illuminated with cobalt‐blue filtered light (Martonyi 2022). In the emergent setting, an examination is performed with a slit lamp biomicroscope or penlight to identify other complicating factors such as microbial infection (manifested as corneal infiltrate), corneal laceration (deep injury into or beyond the corneal epithelium), or the presence of a foreign body (Hamill 2022).

In contrast to trauma, the creation of a corneal epithelial defect is the intended consequence of many commonly performed ocular surgeries, including photorefractive keratectomy (a refractive procedure), superficial keratectomy (for removal of anterior corneal lesions), and corneal cross‐linking (for treatment of keratoconus). Unlike accidental trauma, abrasions created in the setting of ocular surgery have the benefit of a sterile field. Often, adjunctive treatments such as intraoperative topical mitomycin‐C (an anti‐metabolite) and postoperative steroids are used in the setting of surgery to reduce inflammation and scarring. Bandage contact lenses are typically applied for comfort after these types of procedures and are removed when the cornea re‐epithelializes (Chuck 2018; Garcia‐Ferrer 2019).

The human cornea is one of the most densely innervated tissues, with an estimated density of approximately 7000 nerve terminals per square millimeter (Nishida 2022). Approximately 20% of corneal nociceptors are mechanoreceptors that generate acute pain (Shaheen 2014). Regardless of the cause of a corneal abrasion, the dense network of sensory nerve endings in the cornea may result in intense eye pain until full resolution of the defect (Marfurt 2010; Nishida 2022). In a healthy eye, most defects in the corneal epithelium heal fully in 24 to 48 hours by peripheral migrating sheets of epithelial cells, ultimately derived from the limbal epithelial stem cells (Hamill 2022). Although healing often occurs without permanent damage to the cornea, potential complications include recurrent corneal erosions, infectious keratitis, corneal scarring, thinning of corneal stroma, or corneal perforation. These events may require intensive medical or surgical management and can lead to vision loss or loss of the eye. The mainstays of treatment for a corneal abrasion are infection prophylaxis and pain control, coupled with close outpatient follow‐up (Hamill 2022).

Description of the intervention

Although it is standard practice to prescribe topical antimicrobial drops or ointments for corneal abrasions as prophylaxis against infection, there is more variability in practice patterns for the treatment of the pain (Hamill 2022; Sabri 1997). Ointments, bandage contact lenses, and patching of the eye closed under a gauze pad may decrease discomfort by reducing direct exposure of the defect and minimizing the mechanical irritation caused by repeated eyelid movement. It is theorized, however, that patching and bandage contact lenses could potentiate corneal infections by decreasing the cycling of tears over the ocular surface, thereby trapping microbes and impeding the action of host immune factors and antimicrobial medications (Hamill 2022). A Cochrane Review found that patching may not aid with healing or pain control. No conclusions, however, could be drawn about the relative risk of complications (Lim 2016). Bandage contact lenses are another modality of ameliorating pain through barrier coverage while allowing for blinking, normal cosmesis, and the ability to see. In the setting of ocular surface surgeries such as corneal cross‐linking or photorefractive keratectomy, the placement of a bandage contact lens is the standard practice. Although some clinical efficacy and safety of bandage contact lenses have been established in the setting of traumatic corneal abrasions (Menghini 2013; Vandorselaer 2001), it is well‐known that extended contact lens wear increases the risk of infection, and therefore its use may be discouraged for corneal abrasions felt to be high risk for microbial inoculation (Hamill 2022; Poggio 1989; Schein 1989).

Although systemic analgesics such as oral acetaminophen, non‐steroidal anti‐inflammatory drugs (NSAIDs), gabapentin, and opioids are employed for abrasions, topical pharmacologic analgesics have the most direct, local effect on ocular pain with limited systemic side effects. Classes of topical ophthalmic treatments for corneal pain include NSAIDs (ketorolac, diclofenac, indomethacin, bromfenac, flurbiprofen, nepafenac) as well as amide and ester analgesics (tetracaine, proparacaine, and lidocaine). Amide and ester anesthetics act to inhibit electrical conduction on axons by blocking sodium channels on the inner wall of the cell membrane (Levine 2017). The duration of action of these medications is approximately 20 to 30 minutes and would therefore require frequent dosing for use in the outpatient setting to be effective (Levine 2017). This intervention may be performed as an adjuvant to other treatments for corneal analgesia including bandage contact lenses, ointments, patching, topical NSAIDs, or oral analgesics. Here we study the efficacy and safety of topical amide and ester anesthetics for corneal abrasions.

How the intervention might work

Topical ophthalmic amide and ester medications act directly on sensory corneal nerve endings to provide pain relief. In the clinical setting these medications provide immediate relief to ocular surface pain, which can be of diagnostic value in determining the etiology of eye pain while also offering palliation of discomfort to permit a thorough eye exam. Indeed, the immediate effectiveness of these medications also allows for excellent analgesia for a wide variety of ocular procedures (Levine 2017). These analgesic properties may be therapeutic over several days with outpatient use while a corneal epithelial defect heals. Accordingly, a systematic review found that topical NSAIDs for corneal abrasions significantly reduced pain and oral analgesia use without a difference in complications when compared to control (Yu 2021). However, in contrast to anesthetic agents, NSAIDs suppress inflammation, which is not always desirable, particularly where infection may develop.

Why it is important to do this review

Despite potential analgesic benefits from outpatient use of topical ophthalmic amides and esters, their use has become a topic of great controversy. Published case reports and series have identified severe ocular complications associated with the outpatient use of topical anesthetic medications (Aksoy 2013; Chern 1996; Epstein 1968; Khakshoor 2012; Rosenwasser 1990; Varga 1997; Willis 1970). Reported complications include infection, corneal scarring, perforations, and overall ocular morbidity even requiring evisceration or enucleation. In fact, topical anesthetic abuse seems to be a distinct entity with characteristic features such as persistent epithelial defects, corneal stromal ring infiltrates, disproportionate pain, and concurrent substance abuse disorder (Rosenwasser 1990). A person abusing one of these medications may have obtained it in a surreptitious way or may not admit to their use, making the diagnosis of abuse and treatment challenging. In support of these concerns, an intact corneal sensation from the trigeminal nerve is integral to the feedback loop which heals and maintains the ocular surface (Shaheen 2014). People with neurotrophic corneas (decreased or absent corneal sensation often from insults to the trigeminal nerve from herpes simplex virus, varicella‐zoster virus, ocular surgery, neurosurgery, diabetes, or other causes) have chronically high rates of dry eye, non‐healing epithelial defects, microbial keratitis, corneal scarring, corneal thinning, and corneal perforation (Chang 2022). Although the pain response to a corneal abrasion is severe, nociception is one aspect of a protective sensory mechanism that includes increased tear production, the blink reflex, and the stimulation of growth factors important for healing (Chang 2022). The pain itself may serve as a harbinger of a complication, prompting timely presentation to medical care. In addition to interrupting the neural feedback loop, there is evidence that anesthetic medications may be directly cytotoxic to the corneal epithelium, although the full mechanism remains to be studied (Boljka 1994; Parsons 2022; Peyman 1994). Embracing many of these sentiments, a survey of 75 corneal specialists found universal opposition to the outpatient use of topical anesthetics (Lee 2019). Although the collective body of case evidence indicates a syndrome of topical anesthetic abuse (often with devastating consequences), it is unclear whether a strict prohibition is absolutely necessary, or if these medications can be safely administered in a controlled and limited fashion in order to relieve suffering. Given the prevalence of both traumatic and surgically created corneal abrasions, standardization of analgesic strategy for corneal epithelial defects will have broad implications for clinical care. Our goal is to review outcome data from randomized controlled trials (RCTs) of topical amide and ester anesthetics for efficacy of analgesia and safety for corneal epithelial defects resulting from both trauma and ocular surface surgery. Since particularly devastating complications may be rare, pooling data from multiple studies will provide more statistical power to estimate the benefits and risks of use more accurately and precisely than any single RCT.

Objectives

To assess the effectiveness and safety of topical ophthalmic anesthetics compared to placebo or other treatments in persons with corneal abrasions.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs) in this review. We will include all studies reported irrespective of their publication status. We will include within‐person studies, where eyes were randomly allocated to the intervention and comparator.

Types of participants

Participants of all ages who have corneal abrasions of recent onset (within 48 hours) and of varying cause, including the result of accidental trauma and ocular surgery.

Types of interventions

We will include trials comparing topical ophthalmic anesthetics (amide or ester class) to a non‐amide or non‐ester control group (either placebo, non‐treatment, or alternative treatment). We will exclude trials where participants were provided with topical anesthetics only once after trauma‐ or surgery‐induced abrasion because of negligible clinical benefits or harms associated with the transient pharmacological effects of topical anesthetics.

Types of outcome measures

Primary outcomes

Critical outcomes

• Pain control: changes in mean participant‐reported ocular pain as measured using a pain scale that is continuous (e.g. visual analog pain scale) or discrete (e.g. numerical rating scale 1 through 10) from baseline to 24 hours, 48 hours, and 72 hours after treatment initiation. When the change scores are not available, we will use pain scores measured at the above‐mentioned follow‐up time points.

• Epithelial healing: proportion of eyes without complete resolution of epithelial defects by 24 to 72 hours.

• Complications: proportion of eyes/individuals 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.

Secondary outcomes

Important outcomes

• Treatment failure: proportions of participants requiring rescue oral analgesics at 72 hours after treatment initiation.

• Quality of life: mean changes in quality of life as measured by a validated instrument for health‐related or vision‐related quality of life scales, or functions of daily activity as quantified by the 7 or 12 Instrumental Activities of Daily Living checklist, as defined in the original study. We will use data from the longest follow‐up time of the study. When the change scores are not available, we will use mean scores instead.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist will search the following electronic databases for RCTs and controlled clinical trials. There will be no restrictions to language or year of publication.

• Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (the latest issue) (Appendix 1).

• MEDLINE Ovid (1946 to present) (Appendix 2).

• Embase (1947 to present) (Appendix 3).

• PubMed (1948 to present) (Appendix 4).

• Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to present) (Appendix 5).

• US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 6).

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 7).

Searching other resources

We will search the reference lists of studies that are included following full‐text screening. We will also search reference lists of systematic reviews and guidelines for additional trials missed by electronic searches. We will not handsearch specific journals or conference proceedings as many eyes and vision conferences are included in the electronic search of Embase.

Data collection and analysis

Selection of studies

The Information Specialist will perform electronic searches of the selected databases and remove duplicates. Two review authors will work independently to screen the titles and abstracts resulting from the searches using the web‐based software Covidence. They will resolve disagreements by discussion. In general, all citations considered not relevant at this stage will be used only to note their number in the selection of studies flow chart. We will obtain full‐text copies of reports from trials judged to be potentially relevant by either review author. We will correspond with study investigators to clarify study eligibility, as appropriate. For trial registration records and meeting abstracts with no full‐text report, we will contact the study investigators for desired information about study methods and any outcome data that may be available. Whenever study investigators do not respond within two weeks, we will proceed with the information available.

Two review authors independently will assess the full‐text copies of reports for inclusion by applying the Criteria for considering studies for this review. We will resolve disagreements by discussion. For non‐English study reports, we will use Google Translate for initial translation of the methods and results sections of the report and will enlist human translation or refinement as needed. We will not be masked to the names of the authors, institutions, or journal.

We will list all studies excluded during full‐text screening and provide a justification for exclusion. In general, we would expect to list all studies excluded after examination of the full‐text reports in the excluded studies table.

Data extraction and management

Two review authors independently will extract data using an online form developed by Cochrane Eyes and Vision (CEV) in Covidence. We will resolve discrepancies by discussion.

We will contact trial investigators or organizations for desired data that have not been reported and allow two weeks for a response before proceeding with the available data. All data will be imported directly into RevMan Web and one author will verify the accuracy of the data imported.

For multi‐arm studies, we will use data relevant to our intervention and comparator groups, taking care to not double‐count or omit participants. When two randomly allocated trial arms (interventions or comparators) contain relevant data, we will combine data from them using the calculator within RevMan Web. Where data transformation may be required (e.g. standard errors from standard deviations, extracting data presented only in graphs or figures) we will follow the guidance outlined in Chapter 5 and Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021a; Li 2021).

Assessment of risk of bias in included studies

We will assess the potential risk of bias in each included study using Cochrane's RoB 2 tool, as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021b). Two review authors will assess the risk of bias independently using the RoB 2 Excel tool (available from riskofbiasinfo.org). We will compare their judgments and resolve disagreements by discussion. We will assess bias for the 'intention‐to‐treat effect' for the efficacy outcome of pain control.

We will consider and assess risk of bias in the following domains:

• bias due to the randomization process;

• bias due to deviations from the intended intervention;

• bias due to missing outcome data;

• bias in measurement of the outcome; and

• bias in selection of the reported result.

Based on these five domains, we will assign an overall risk of bias judgment of 'high', 'some concerns', or 'low' risk of bias.

Measures of treatment effect

We will refer to guidance outlined in Chapters 9 and 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2021; McKenzie 2021). We will calculate the risk ratio (RR) and 95% confidence intervals (95% CIs) for dichotomous outcomes (proportion of eyes without full epithelial healing at 24 to 72 hours). We will calculate the mean difference (MD) and 95% CIs for continuous outcomes (changes in pain scores from baseline to 24, 48, and 72 hours after treatment; risk of adverse events per person‐time at furthest time point). We will calculate the standardized mean difference (SMD) and 95% CIs for continuous outcomes measured using different scales (e.g. mean change in quality of life or activities of daily living). Where possible, we will check for the skewness of continuous data (Altman 1996).

Unit of analysis issues

We will refer to Chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021c) where variations on RCTs are included. If a study randomizes both eyes of participants (to the same or different interventions), we will extract the results that accounted for the correlation between eyes. If the primary studies failed to consider the correlation between two eyes, we will exclude those studies in the sensitivity analysis.

Dealing with missing data

Our goal is to conduct intention‐to‐treat (ITT) analyses. We will request missing data from study authors and allow two weeks for a response before proceeding with available data. We will use imputed data only when they are computed by the trial investigators using an appropriate method; we will not impute missing data ourselves. When ITT data are not available, we will do an available‐cases analysis. This approach assumes that data are missing at random. We will assess whether this assumption is reasonable by collecting data from each included trial on the number of participants excluded or lost to follow‐up and reasons for loss to follow‐up by treatment group when reported. This information will also be used when we assess the potential risk of bias in an individual trial (Higgins 2021b).

Assessment of heterogeneity

We will examine the overall characteristics of the studies and participants, in particular the type of participants and types of interventions, to assess the extent to which the studies are similar enough to make pooling study results in meta‐analyses sensible.

We will examine the forest plots of study results for consistency of effect estimates from individual studies, in particular considering the size and direction of effects and overlap of confidence intervals. We will calculate I^2, which is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) (Higgins 2002). We will consider I² values over 75% to indicate considerable heterogeneity but will also consider Chi² and P values (Deeks 2021).

Assessment of reporting biases

When there are 10 trials or more included in a meta‐analysis, we will construct funnel plots and consider tests for asymmetry to assess small study effect, which may be due to publication bias, according to Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Page 2021). Selective reporting of results will be judged during assessment of potential risk of bias.

Data synthesis

We will refer to Chapters 9 and 10 of the Cochrane Handbook for Systematic Reviews of Interventions for data synthesis (Deeks 2021; McKenzie 2021). We will pool data using a random‐effects model in RevMan Web. When data are sparse (fewer than three trials), we will use a fixed‐effect model for meta‐analysis of outcomes.

Whenever there is substantial heterogeneity among individual study effect estimates, such that a combined result may not provide a good summary of the individual trial results, we will not pool the data but will describe the pattern of the individual study results. If there is evidence of statistical heterogeneity but all the effect estimates are in the same direction such that a combined estimate would seem to provide a good summary of the individual trial results, we may combine the data.

Subgroup analysis and investigation of heterogeneity

If there is sufficient information in 10 or more included trials, we will perform subgroup analysis on 'pain control' and 'epithelial healing' by each of the following covariates separately:

• etiology of corneal abrasion: ocular surgery or trauma;

• equity considerations: sex or race, depending on the availability of data;

• exposure to intervention medications such as duration of use (24 to 48 hours versus 48 hours or longer); frequency of use (2 to 3 times per day versus ≥ 4 times per day); concentration of anesthetic (diluted versus standard concentration).

Sensitivity analysis

If reasonable, we will perform sensitivity analyses by:

• excluding studies judged to be at an overall high risk of bias, and

• excluding within‐person studies that do not address correlation of both eyes when reporting the trial results.

Summary of findings and assessment of the certainty of the evidence

We will prepare a summary of findings tables presenting relative and absolute risks (Schünemann 2021). Two review authors will grade independently the overall certainty of the evidence for the following efficacy and safety outcomes using the GRADE classification (GRADEpro GDT ):

• efficacy outcomes: changes in mean participant‐reported ocular pain from baseline to 24 hours, 48 hours, and 72 hours after treatment initiation;

• safety outcomes: we will choose between the two safety outcomes in the following order of preference, based on available study reporting:

  • risk of adverse events per person‐time at furthest time point; or

  • the proportion of eyes without complete resolution of epithelial defects by 24 to 72 hours.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Cornea] explode all trees
#2 MeSH descriptor: [Corneal Diseases] explode all trees
#3 MeSH descriptor: [Epithelium, Corneal] explode all trees
#4 MeSH descriptor: [Keratectomy] explode all trees
#5 MeSH descriptor: [Refractive Surgical Procedures] explode all trees
#6 cornea*
#7 (ocular NEXT/1 (surface* or epithelia*)) or keratectom* or keratoplast* or "cross linking"
#8 MeSH descriptor: [Eye Injuries] explode all trees
#9 Eye* NEXT/3 (injur* or abrasion* or erosion* or trauma* or wound* or (foreign NEXT/1 bod*) or (epithelial NEXT/1 defect*) or lesion* or laceration or surger* or surgical)
#10 {OR #1‐#9}
#11 MeSH descriptor: [Amides] explode all trees
#12 MeSH descriptor: [Esters] explode all trees
#13 amide OR amides OR ester OR esters
#14 topical NEXT/2 (analgesic* or anesthetic* or anaesthetic*)
#15 MeSH descriptor: [Tetracaine] explode all trees
#16 "ak‐t‐caine" OR amethocaine OR ametocaine OR ametop OR anetaine OR anethaine OR butethanol OR butethol OR contralgin OR curtacaine OR decicain OR decicaine OR "dextrose‐pontocaine hcl" OR dicain OR dicaine OR fissucain OR gingicain OR intercain OR landocaine OR laudocaine OR meethobalm OR mucaesthin OR niphanoid OR pantocain OR pantocaine OR pontocaine OR rexocaine OR tetocaine OR tetracain OR tetracaine OR tetrakain OR tetrracaine OR tonexol OR uromucaesthin OR "136‐47‐0" OR "94‐24‐6"
#17 alcaine OR anestalcon OR "chibro‐kerakain" OR kainair OR keracaine OR miraxil OR "ocu‐caine" OR oftetic OR ophthaine OR ophthetic OR opthetic OR "poen‐caina" OR proparacain OR proparacaine OR proporacaine OR proxymetacaine OR "499‐67‐2" OR "5875‐06‐9"
#18 MeSH descriptor: [Lidocaine] explode all trees
#19 akten OR "algrx 3268" OR algrx3268 OR alphacaine OR anestacaine OR anestacon OR anestacone OR aritmal OR betacaine OR cidancaina OR "col 1077" OR col1077 OR "corus 1030" OR corus1030 OR dalcaine OR dentipatch OR dolicaine OR duncaine OR dynexan OR "ela‐max" OR esracain OR esracaine OR farmacaina OR "gesicain jelly" OR "gesicain ointment" OR "gesicain viscous" OR glydo OR gravocain OR isicaine OR jetocaine OR jetokain OR "l‐caine" OR lecasin OR leostesin OR "lida mantle" OR lidbree OR lidocain OR lidocaine OR lidocaton OR lidocor OR lidocorit OR lidoderm OR lidonest OR lidopain OR lidopen OR lidorx OR lidothesin OR lignocaine OR lignostab OR lincaine OR liquocaine OR liris OR "ll 30" OR ll30 OR "lmx 4" OR "lmx 5" OR "lta ii kit" OR maricaine OR "neo novutox" OR neolidocaton OR Octocaine OR otipax OR "paediatric lta kit" OR "pediatric lta kit" OR penles OR radiaguard OR ralvo OR "remicaine gel" OR roxicaina OR rucaina OR ruciana OR solarcaine OR solcaine OR "sp 103" OR sp103 OR truxacaine OR "uad caine" OR vasocaine OR versatis OR xidocaine OR xilina OR xiline OR xilocaina OR "xilonest pomade" OR "xilotane gel" OR xilyne OR xylcaine OR xylestesin OR Xylesthesin OR xylocain OR xylocaina OR xylocaine OR xylocard OR xylocitin OR xyloctin OR xyloneural OR xylonor OR "xyloproct n" OR xyloton OR xylotox OR xylyne OR zingo OR ztlido OR "137‐58‐6" OR "24847‐67‐4" OR "56934‐02‐2" OR "73‐78‐9"
#20 Oxybuprocaine OR benoxil OR benoxinate OR cebesine OR conjucain OR conjuncain OR dorsacain OR dorsacaine OR lacrimin OR novesin OR novesine OR oxibuprocainum OR oxibuprokain OR oxybucaine OR prescaina OR "5987‐82‐6" OR "99‐43‐4"
#21 MeSH descriptor: [Cocaine] this term only
#22 Cocaine OR cocain OR codrenine OR erythroxylin OR goprelto OR locosthetic OR neurocaine OR numbrino OR sterilocaine OR "50‐36‐2" OR "53‐21‐4" OR "5937‐29‐1"
#23 {OR #11‐#22}
#24 #10 AND #23 in Trials

Appendix 2. MEDLINE Ovid search strategy

1. Randomized Controlled Trial.pt.
2. Controlled Clinical Trial.pt.
3. (randomized or randomised).ab,ti.
4. placebo.ab,ti.
5. drug therapy.fs.
6. randomly.ab,ti.
7. trial.ab,ti.
8. groups.ab,ti.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. exp animals/ not humans.sh.
11. 9 not 10
12. exp Cornea/
13. exp Corneal Diseases/
14. exp Epithelium, Corneal/
15. exp Keratectomy/
16. exp Refractive Surgical Procedures/
17. cornea*.tw.
18. ((ocular adj1 (surface* or epithelia*)) or keratectom* or keratoplast* or "cross linking").tw.
19. exp eye injuries/
20. (Eye* adj3 (injur* or abrasion* or erosion* or trauma* or wound* or foreign bod* or "epithelial defect*" or lesion* or laceration or surger* or surgical)).tw.
21. or/12‐20
22. exp Amides/
23. exp Esters/
24. (amide or amides or ester or esters).tw.
25. (topical adj2 (analgesic* or anesthetic* or anaesthetic*)).tw.
26. exp Tetracaine/
27. ("ak‐t‐caine" or amethocaine or ametocaine or ametop or anetaine or anethaine or butethanol or butethol or contralgin or curtacaine or decicain or decicaine or "dextrose‐pontocaine hcl" or dicain or dicaine or fissucain or gingicain or intercain or landocaine or laudocaine or meethobalm or mucaesthin or niphanoid or pantocain or pantocaine or pontocaine or rexocaine or tetocaine or tetracain or tetracaine or tetrakain or tetrracaine or tonexol or uromucaesthin or "136‐47‐0" or "94‐24‐6").tw,rn.
28. (alcaine or anestalcon or "chibro‐kerakain" or kainair or keracaine or miraxil or "ocu‐caine" or oftetic or ophthaine or ophthetic or opthetic or "poen‐caina" or proparacain or proparacaine or proporacaine or proxymetacaine or "499‐67‐2" or "5875‐06‐9").tw,rn.
29. exp Lidocaine/
30. (akten or "algrx 3268" or algrx3268 or alphacaine or anestacaine or anestacon or anestacone or aritmal or betacaine or cidancaina or "col 1077" or col1077 or "corus 1030" or corus1030 or dalcaine or dentipatch or dolicaine or duncaine or dynexan or "ela‐max" or esracain or esracaine or farmacaina or "gesicain jelly" or "gesicain ointment" or "gesicain viscous" or glydo or gravocain or isicaine or jetocaine or jetokain or "l‐caine" or lecasin or leostesin or "lida mantle" or lidbree or lidocain or lidocaine or lidocaton or lidocor or lidocorit or lidoderm or lidonest or lidopain or lidopen or lidorx or lidothesin or lignocaine or lignostab or lincaine or liquocaine or liris or "ll 30" or ll30 or "lmx 4" or "lmx 5" or "lta ii kit" or maricaine or "neo novutox" or neolidocaton or Octocaine or otipax or "paediatric lta kit" or "pediatric lta kit" or penles or radiaguard or ralvo or "remicaine gel" or roxicaina or rucaina or ruciana or solarcaine or solcaine or "sp 103" or sp103 or truxacaine or "uad caine" or vasocaine or versatis or xidocaine or xilina or xiline or xilocaina or "xilonest pomade" or "xilotane gel" or xilyne or xylcaine or xylestesin or Xylesthesin or xylocain or xylocaina or xylocaine or xylocard or xylocitin or xyloctin or xyloneural or xylonor or "xyloproct n" or xyloton or xylotox or xylyne or zingo or ztlido or "137‐58‐6" or "24847‐67‐4" or "56934‐02‐2" or "73‐78‐9").tw,rn.
31. (Oxybuprocaine or benoxil or benoxinate or cebesine or conjucain or conjuncain or dorsacain or dorsacaine or lacrimin or novesin or novesine or oxibuprocainum or oxibuprokain or oxybucaine or prescaina or "5987‐82‐6" or "99‐43‐4").tw,rn.
32. cocaine/
33. (Cocaine or cocain or codrenine or erythroxylin or goprelto or locosthetic or neurocaine or numbrino or sterilocaine or "50‐36‐2" or "53‐21‐4" or "5937‐29‐1").tw,rn.
34. or/22‐33
35. 21 and 34
36. 11 and 35

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville (Glanville 2006).

Appendix 3. EMBASE.com search strategy

#1 'randomized controlled trial'/exp
#2 'randomization'/exp
#3 'double blind procedure'/exp
#4 'single blind procedure'/exp
#5 random*:ab,ti
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 'animal'/exp OR 'animal experiment'/exp
#8 'human'/exp
#9 #7 AND #8
#10 #7 NOT #9
#11 #6 NOT #10
#12 'clinical trial'/exp
#13 (clin* NEAR/3 trial*):ab,ti
#14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti
#15 'placebo'/exp
#16 placebo*:ab,ti
#17 random*:ab,ti
#18 'experimental design'/exp
#19 'crossover procedure'/exp
#20 'control group'/exp
#21 'latin square design'/exp
#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23 #22 NOT #10
#24 #23 NOT #11
#25 'comparative study'/exp
#26 'evaluation'/exp
#27 'prospective study'/exp
#28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti
#29 #25 OR #26 OR #27 OR #28
#30 #29 NOT #10
#31 #30 NOT (#11 OR #23)
#32 #11 OR #24 OR #31
#33 'cornea'/exp
#34 'cornea disease'/exp
#35 'cornea epithelium'/exp
#36 'cornea surgery'/exp
#37 'refractive surgery'/exp
#38 Cornea*:ab,ti,kw
#39 (ocular NEXT/1 (surface* or epithelia*)):ab,ti,kw or (keratectom* or keratoplast* or "cross linking"):ab,ti,kw
#40 'eye injury'/exp
#41 (Eye* NEXT/3 (injur* or abrasion* or erosion* or trauma* or wound* or "foreign bod*" or "epithelial defect*" or lesion* or laceration or surger* or surgical)):ab,ti,kw
#42 #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41
#43 'amide'/exp
#44 'ester'/exp
#45 (amide OR amides OR ester OR esters):ab,ti,kw
#46 'tetracaine'/exp
#47 ("ak‐t‐caine" OR amethocaine OR ametocaine OR ametop OR anetaine OR anethaine OR butethanol OR butethol OR contralgin OR curtacaine OR decicain OR decicaine OR "dextrose‐pontocaine hcl" OR dicain OR dicaine OR fissucain OR gingicain OR intercain OR landocaine OR laudocaine OR meethobalm OR mucaesthin OR niphanoid OR pantocain OR pantocaine OR pontocaine OR rexocaine OR tetocaine OR tetracain OR tetracaine OR tetrakain OR tetrracaine OR tonexol OR uromucaesthin OR "136‐47‐0" OR "94‐24‐6"):ab,ti,kw,tn
#48 'proxymetacaine'/exp
#49 (alcaine OR anestalcon OR "chibro‐kerakain" OR kainair OR keracaine OR miraxil OR "ocu‐caine" OR oftetic OR ophthaine OR ophthetic OR opthetic OR "poen‐caina" OR proparacain OR proparacaine OR proporacaine OR proxymetacaine OR "499‐67‐2" OR "5875‐06‐9"):ab,ti,kw,tn
#50 'lidocaine'/exp
#51 (akten OR "algrx 3268" OR algrx3268 OR alphacaine OR anestacaine OR anestacon OR anestacone OR aritmal OR betacaine OR cidancaina OR "col 1077" OR col1077 OR "corus 1030" OR corus1030 OR dalcaine OR dentipatch OR dolicaine OR duncaine OR dynexan OR "ela‐max" OR esracain OR esracaine OR farmacaina OR "gesicain jelly" OR "gesicain ointment" OR "gesicain viscous" OR glydo OR gravocain OR isicaine OR jetocaine OR jetokain OR "l‐caine" OR lecasin OR leostesin OR "lida mantle" OR lidbree OR lidocain OR lidocaine OR lidocaton OR lidocor OR lidocorit OR lidoderm OR lidonest OR lidopain OR lidopen OR lidorx OR lidothesin OR lignocaine OR lignostab OR lincaine OR liquocaine OR liris OR "ll 30" OR ll30 OR "lmx 4" OR "lmx 5" OR "lta ii kit" OR maricaine OR "neo novutox" OR neolidocaton OR Octocaine OR otipax OR "paediatric lta kit" OR "pediatric lta kit" OR penles OR radiaguard OR ralvo OR "remicaine gel" OR roxicaina OR rucaina OR ruciana OR solarcaine OR solcaine OR "sp 103" OR sp103 OR truxacaine OR "uad caine" OR vasocaine OR versatis OR xidocaine OR xilina OR xiline OR xilocaina OR "xilonest pomade" OR "xilotane gel" OR xilyne OR xylcaine OR xylestesin OR Xylesthesin OR xylocain OR xylocaina OR xylocaine OR xylocard OR xylocitin OR xyloctin OR xyloneural OR xylonor OR "xyloproct n" OR xyloton OR xylotox OR xylyne OR zingo OR ztlido OR "137‐58‐6" OR "24847‐67‐4" OR "56934‐02‐2" OR "73‐78‐9"):ab,ti,kw,tn
#52 'oxybuprocaine'/exp
#53 (Oxybuprocaine OR benoxil OR benoxinate OR cebesine OR conjucain OR conjuncain OR dorsacain OR dorsacaine OR lacrimin OR novesin OR novesine OR oxibuprocainum OR oxibuprokain OR oxybucaine OR prescaina OR "5987‐82‐6" OR "99‐43‐4"):ab,ti,kw,tn
#54 'cocaine'/exp
#55 (Cocaine OR cocain OR codrenine OR erythroxylin OR goprelto OR locosthetic OR neurocaine OR numbrino OR sterilocaine OR "50‐36‐2" OR "53‐21‐4" OR "5937‐29‐1"):ab,ti,kw,tn
#56 #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55
#57 #42 AND #56
#58 #32 AND #57

Appendix 4. PubMed search strategy

#1 ((randomized controlled trial[pt]) OR (controlled clinical trial[pt]) OR (randomised[tiab] OR randomized[tiab]) OR (placebo[tiab]) OR (drug therapy[sh]) OR (randomly[tiab]) OR (trial[tiab]) OR (groups[tiab])) NOT (animals[mh] NOT humans[mh])
#2 cornea*[tw]
#3 (ocular[tw] AND (surface*[tw] OR epithelia*[tw])) OR keratectom*[tw] OR keratoplast*[tw] OR "cross linking"[tw]
#4 (eye[tw] OR eyes[tw] OR eyelid*[tw]) AND (injur*[tw] OR abrasion*[tw] OR erosion*[tw] OR trauma*[tw] OR wound*[tw] OR "foreign bod*"[tw] OR "epithelial defect*"[tw] OR lesion*[tw] OR laceration*[tw] OR surger*[tw] OR surgical[tw])
#5 #2 OR #3 OR #4
#6 (amide[tw] OR amides[tw] OR ester[tw] OR esters[tw])
#7 ("ak‐t‐caine"[tw] OR amethocaine[tw] OR ametocaine[tw] OR ametop[tw] OR anetaine[tw] OR anethaine[tw] OR butethanol[tw] OR butethol[tw] OR contralgin[tw] OR curtacaine[tw] OR decicain[tw] OR decicaine[tw] OR "dextrose‐pontocaine hcl"[tw] OR dicain[tw] OR dicaine[tw] OR fissucain[tw] OR gingicain[tw] OR intercain[tw] OR landocaine[tw] OR laudocaine[tw] OR meethobalm[tw] OR mucaesthin[tw] OR niphanoid[tw] OR pantocain[tw] OR pantocaine[tw] OR pontocaine[tw] OR rexocaine[tw] OR tetocaine[tw] OR tetracain[tw] OR tetracaine[tw] OR tetrakain[tw] OR tetrracaine[tw] OR tonexol[tw] OR uromucaesthin[tw] OR "136‐47‐0"[tw] OR "94‐24‐6"[tw])
#8 (alcaine[tw] OR anestalcon[tw] OR "chibro‐kerakain"[tw] OR kainair[tw] OR keracaine[tw] OR miraxil[tw] OR "ocu‐caine"[tw] OR oftetic[tw] OR ophthaine[tw] OR ophthetic[tw] OR opthetic[tw] OR "poen‐caina"[tw] OR proparacain[tw] OR proparacaine[tw] OR proporacaine[tw] OR proxymetacaine[tw] OR "499‐67‐2"[tw] OR "5875‐06‐9"[tw])
#9 (akten[tw] OR "algrx 3268"[tw] OR algrx3268[tw] OR alphacaine[tw] OR anestacaine[tw] OR anestacon[tw] OR anestacone[tw] OR aritmal[tw] OR betacaine[tw] OR cidancaina[tw] OR "col 1077"[tw] OR col1077[tw] OR "corus 1030"[tw] OR corus1030[tw] OR dalcaine[tw] OR dentipatch[tw] OR dolicaine[tw] OR duncaine[tw] OR dynexan[tw] OR "ela‐max"[tw] OR esracain[tw] OR esracaine[tw] OR farmacaina[tw] OR "gesicain jelly"[tw] OR "gesicain ointment"[tw] OR "gesicain viscous"[tw] OR glydo[tw] OR gravocain[tw] OR isicaine[tw] OR jetocaine[tw] OR jetokain[tw] OR "l‐caine"[tw] OR lecasin[tw] OR leostesin[tw] OR "lida mantle"[tw] OR lidbree[tw] OR lidocain[tw] OR lidocaine[tw] OR lidocaton[tw] OR lidocor[tw] OR lidocorit[tw] OR lidoderm[tw] OR lidonest[tw] OR lidopain[tw] OR lidopen[tw] OR lidorx[tw] OR lidothesin[tw] OR lignocaine[tw] OR lignostab[tw] OR lincaine[tw] OR liquocaine[tw] OR liris[tw] OR "ll 30"[tw] OR ll30[tw] OR "lmx 4"[tw] OR "lmx 5"[tw] OR "lta ii kit"[tw] OR maricaine[tw] OR "neo novutox"[tw] OR neolidocaton[tw] OR Octocaine[tw] OR otipax[tw] OR "paediatric lta kit"[tw] OR "pediatric lta kit"[tw] OR penles[tw] OR radiaguard[tw] OR ralvo[tw] OR "remicaine gel"[tw] OR roxicaina[tw] OR rucaina[tw] OR ruciana[tw] OR solarcaine[tw] OR solcaine[tw] OR "sp 103"[tw] OR sp103[tw] OR truxacaine[tw] OR "uad caine"[tw] OR vasocaine[tw] OR versatis[tw] OR xidocaine[tw] OR xilina[tw] OR xiline[tw] OR xilocaina[tw] OR "xilonest pomade"[tw] OR "xilotane gel"[tw] OR xilyne[tw] OR xylcaine[tw] OR xylestesin[tw] OR Xylesthesin[tw] OR xylocain[tw] OR xylocaina[tw] OR xylocaine[tw] OR xylocard[tw] OR xylocitin[tw] OR xyloctin[tw] OR xyloneural[tw] OR xylonor[tw] OR "xyloproct n"[tw] OR xyloton[tw] OR xylotox[tw] OR xylyne[tw] OR zingo[tw] OR ztlido[tw] OR "137‐58‐6"[tw] OR "24847‐67‐4"[tw] OR "56934‐02‐2"[tw] OR "73‐78‐9"[tw])
#10 oxybuprocaine[tw] OR benoxil[tw] OR benoxinate[tw] OR cebesine[tw] OR conjucain[tw] OR conjuncain[tw] OR dorsacain[tw] OR dorsacaine[tw] OR lacrimin[tw] OR novesin[tw] OR novesine[tw] OR oxibuprocainum[tw] OR oxibuprokain[tw] OR oxybucaine[tw] OR prescaina[tw] OR "5987‐82‐6"[tw] OR "99‐43‐4"[tw]
#11 cocaine[tw] OR cocain[tw] OR codrenine[tw] OR erythroxylin[tw] OR goprelto[tw] OR locosthetic[tw] OR neurocaine[tw] OR numbrino[tw] OR sterilocaine[tw] OR "50‐36‐2"[tw] OR "53‐21‐4"[tw] OR "5937‐29‐1"[tw]
#12 #6 OR #7 OR #8 OR #9 OR #10 OR #11
#13 #1 AND #5 AND #12
#14 Medline[sb]
#15 #13 NOT #14

Appendix 5. LILACS search strategy

(MH:A09.371.060.217$ OR MH:C11.204$ OR MH:A09.371.060.217.325$ OR MH:A10.272.510$ OR MH:E04.378$ OR MH:E04.540.825$ OR MH:C10.900.300.284.250$ OR MH:C11.297$ OR MH:C26.915.300.425.250$ OR cornea$ OR (ocular surface$) OR (epithelia$ surface$) OR keratectomy$ OR keratoplasty$ OR "cross linking" OR (Eye$ AND (injur$ OR abrasion$ OR erosion$ OR trauma$ OR wound$ OR "foreign body" OR "foreign bodies" OR "epithelial defect" OR lesion$ OR laceration OR surger$ OR surgical))) AND (Amides OR amidas OR MH:D02.065$ OR Esters OR esters OR MH:D02.241.400$ OR MH:SP4.097.036.654$ OR Tetracaine OR Tetracaina OR MH: D02.241.223.100.050.500.968$ OR MH: D02.455.426.559.389.127.020.937.968$ OR "ak‐t‐caine" OR amethocaine OR ametocaine OR ametop OR anetaine OR anethaine OR butethanol OR butethol OR contralgin OR curtacaine OR decicain OR decicaine OR "dextrose‐pontocaine hcl" OR dicain OR dicaine OR fissucain OR gingicain OR intercain OR landocaine OR laudocaine OR meethobalm OR mucaesthin OR niphanoid OR pantocain OR pantocaine OR pontocaine OR rexocaine OR tetocaine OR tetracain OR tetracaine OR tetrakain OR tetrracaine OR tonexol OR uromucaesthin OR "136‐47‐0" OR "94‐24‐6" OR proparacaine OR alcaine OR anestalcon OR "chibro‐kerakain" OR kainair OR keracaine OR miraxil OR "ocu‐caine" OR oftetic OR ophthaine OR ophthetic OR opthetic OR "poen‐caina" OR proparacain OR proporacaine OR proxymetacaine OR "499‐67‐2" OR "5875‐06‐9" OR Lidocaine OR Lidocaina OR MH:D02.065.199.092.500$ OR MH: D02.092.146.113.092.500$ OR akten OR "algrx 3268" OR algrx3268 OR alphacaine OR anestacaine OR anestacon OR anestacone OR aritmal OR betacaine OR cidancaina OR "col 1077" OR col1077 OR "corus 1030" OR corus1030 OR dalcaine OR dentipatch OR dolicaine OR duncaine OR dynexan OR "ela‐max" OR esracain OR esracaine OR farmacaina OR "gesicain jelly" OR "gesicain ointment" OR "gesicain viscous" OR glydo OR gravocain OR isicaine OR jetocaine OR jetokain OR "l‐caine" OR lecasin OR leostesin OR "lida mantle" OR lidbree OR lidocain OR lidocaine OR lidocaton OR lidocor OR lidocorit OR lidoderm OR lidonest OR lidopain OR lidopen OR lidorx OR lidothesin OR lignocaine OR lignostab OR lincaine OR liquocaine OR liris OR "ll 30" OR ll30 OR "lmx 4" OR "lmx 5" OR "lta ii kit" OR maricaine OR "neo novutox" OR neolidocaton OR Octocaine OR otipax OR "paediatric lta kit" OR "pediatric lta kit" OR penles OR radiaguard OR ralvo OR "remicaine gel" OR roxicaina OR rucaina OR ruciana OR solarcaine OR solcaine OR "sp 103" OR sp103 OR truxacaine OR "uad caine" OR vasocaine OR versatis OR xidocaine OR xilina OR xiline OR xilocaina OR "xilonest pomade" OR "xilotane gel" OR xilyne OR xylcaine OR xylestesin OR Xylesthesin OR xylocain OR xylocaina OR xylocaine OR xylocard OR xylocitin OR xyloctin OR xyloneural OR xylonor OR "xyloproct n" OR xyloton OR xylotox OR xylyne OR zingo OR ztlido OR "137‐58‐6" OR "24847‐67‐4" OR "56934‐02‐2" OR "73‐78‐9" OR Oxybuprocaine OR benoxil OR benoxinate OR cebesine OR conjucain OR conjuncain OR dorsacain OR dorsacaine OR lacrimin OR novesin OR novesine OR oxibuprocainum OR oxibuprokain OR oxybucaine OR prescaina OR "5987‐82‐6" OR "99‐43‐4" OR Cocaine OR cocain OR codrenine OR erythroxylin OR goprelto OR locosthetic OR neurocaine OR numbrino OR sterilocaine OR "50‐36‐2" OR "53‐21‐4" OR "5937‐29‐1")

Appendix 6. ClinicalTrials.gov search strategy

((cornea OR corneal OR ocular surface OR ocular epithelial OR ocular epithelium OR keratectomy OR keratoplasty OR "cross linking") OR (eye AND (injury OR abrasion OR erosion OR trauma OR wound OR "foreign body" OR "epithelial defect" OR lesion OR laceration OR surgery OR surgical))) AND (Amide OR ester OR tetracaine OR proparacaine OR lidocaine OR oxybuprocaine OR cocaine)

Appendix 7. WHO ICTRP search strategy

corneal AND amide OR corneal AND ester OR corneal AND tetracaine OR corneal AND proparacaine OR corneal AND lidocaine OR corneal AND oxybuprocaine OR corneal AND cocaine

cornea AND amide OR cornea AND ester OR cornea AND tetracaine OR cornea AND proparacaine OR cornea AND lidocaine OR cornea AND oxybuprocaine OR cornea AND cocaine

eye injury AND amide OR eye injury AND ester OR eye injury AND tetracaine OR eye injury AND proparacaine OR eye injury AND lidocaine OR eye injury AND oxybuprocaine OR eye injury AND cocaine

ocular surface AND amide OR ocular surface AND ester OR ocular surface AND tetracaine OR ocular surface AND proparacaine OR ocular surface AND lidocaine OR ocular surface AND oxybuprocaine OR ocular surface AND cocaine

keratectomy AND amide OR keratectomy AND ester OR keratectomy AND tetracaine OR keratectomy AND proparacaine OR keratectomy AND lidocaine OR keratectomy AND oxybuprocaine OR keratectomy AND cocaine

keratoplasty AND amide OR keratoplasty AND ester OR keratoplasty AND tetracaine OR keratoplasty AND proparacaine OR keratoplasty AND lidocaine OR keratoplasty AND oxybuprocaine OR keratoplasty AND cocaine

Contributions of authors

Conception and design of the review: Michael Sulewski (MS), Cristos Ifantides (CI), Su‐Hsun Liu (SL), Louis Leslie (LL), and Irene C Kuo (IK).
Drafting the protocol or providing critical comments: MS, CI, SL, LL, and IK.
Final approval of the protocol: MS, CI, SL, LL, and IK.

Sources of support

Internal sources

• No sources of support provided

External sources

• National Eye Institute, National Institutes of Health, USA, USA

  Cochrane Eyes and Vision US Project, supported by grant UG1EY020522 (PI: Tianjing Li, MD, MHS, PhD)

• Queen’s University Belfast, UK

  Gianni Virgili, Co‐ordinating Editor for Cochrane Eyes and Vision’s work is funded by the Centre for Public Health, Queen’s University of Belfast, Northern Ireland

• Public Health Agency, UK

  The HSC Research and Development (R&D) Division of the Public Health Agency funds the Cochrane Eyes and Vision editorial base at Queen's University Belfast.

Declarations of interest

• Michael Sulewski: declared that he has no conflict of interest.

• Cristos Ifantides: reported ownership of stock in Pfizer. His partner works for AbbVie, a manufacturer of eye medications, but the partner does not work in the eye care space.

• Su‐Hsun Liu: reported a grant from the National Eye Institute, National Institutes of Health, USA; payment to institution.

• Louis Leslie: declared he has no conflict of interest.

• Irene C Kuo: reported consulting fees from Okogen (one‐time discussion re: therapy/structuring trials for treatment of adenoviral conjunctivitis) and Novan (one‐time phone conversation re: therapy for adenoviral conjunctivitis); personal payments.

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