Control of Pain in Intravitreal Injections (COPIVIN Study): A Study Evaluating the Use of Combination Topical Anesthetic and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Phase: PHASE4
Conditions: Intravitreal Injections, IVI
Sponsor: University of Wisconsin, Madison

 
 
 
 
 
 
 
 
 
 
A Pilot Study: Control of pain in intravitreal injections using topical 
NSAIDs (COPIVIN) 
 
NCT04343222 
 
Protocol Version date 
April 24, 2019 
 

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A Pilot Study: Control of pain in intravitreal injections using topical 
NSAIDs (COPIVIN) 
 
Title  
A Pilot Study: Control of pain in intravitreal injections using topical NSAIDs (COPIVIN) 
 
PI Name and Institutional Affiliation 
Mihai Mititelu, MD, MPH, Assistant Professor (CHS), Department of Ophthalmology and 
Visual Sciences, University of Wisconsin School of Medicine and Public Health 
 
Protocol Version date 
April 24, 2019 
 
Co-Investigator(s) 
Maxwell Wingelaar, MD 
Jonathan Chang, MD 
 
Study Coordinator(s)  
Clinical Eye Research Unit study coordinator staff 
 
Funding Sponsor 
Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison 
 
Project Summary 
Intravitreal injections are a very common form of treatment for a variety of ocular 
pathologies. The use of these injections has only increased given the large utility they 
provide. They both improved visual outcomes and provided patients an overall better 
quality of life. However, a problem experienced by patients who undergo these 
injections is the need for multiple reoccurring injections to maintain control of their 
disease.1,2,3 It has long been an issue to provide patients optimal pain relief both during 
and after their intravitreal injections. Topical anesthesia is often utilized through frequent 
rounds of proparacaine eye drops. Other providers often use Lidocaine gel or 
Lidocaine-soaked cotton swaps with variable results in terms of pain control.2,4 
Subconjunctival lidocaine has also been utilized with variable control of pain, however 
patients did report anxiety with the thought of being given an additional injection.5,6 
Patient pain is subjective and difficult to objectively quantify when comparing different 
methods of post-injection control. One commonly employed pain rating system is the 
Wong-Baker FACES pain scale which has been quite successful in objectively 
quantifying patient discomfort.5,6 It should be noted that this scale is only reliable in a 
patient whom is able to understand how the scale works. Other research studies have 
shown adequate to improved pain control through the use of topical non-steroidal anti-
inflammatory drug (NSAID) eye drops. One study looked at the use of topical 
Nepafenac 0.10% on post injection pain.8 This study used the McGill pain assessment 
questionnaire, which not only quantified pain but the additional benefit of describing the 
nature of the pain the patient experienced. In a clinical research study, Makri et al 
looked at pain immediately and 6 hours after injection. The researchers found that when 

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compared to the control group (artificial tears) the group who received NSAID eye drops 
had better pain control.8,1 In a similar study, Bromfenac, another topical NSAID eye 
drop, provided good pain relief post injection, setting a precedent for the use of topical 
NSAIDs in controlling IVI pain.10 
 
However, studies have only reported pain relief immediately and 6 hours after 
injection.10 There have not been any studies showing pain control 24 hours post 
injection. Furthermore, no studies to date have compared the timing of application of a 
topical NSAID, in the alleviation of long-term pain patients experience. Bromfenac 
0.09% is our agent of choice given its previously demonstrated effectiveness in pain 
control and also strength when compared to other ophthalmic NSAIDs.10 This was 
demonstrated in a paper by Sheppard that compared Bromfenac with other topical 
NSAID eye drops and proved that it offered approximately 3-4 times higher levels of 
COX-2 inhibition.13 It has been approved by the FDA as a one time daily eye drop to 
reduce inflammation.14 It is commonly utilized following cataract surgery to help reduce 
intraocular inflammation. Our study looks at this medication’s utility to control pain 
following IVI, another invasive procedure. We would assess pain control immediately 
following injection, 6 hours post injection and 24 hours post injection. This will allow us 
to evaluate Bromfenac 0.09%’s effectiveness on overall immediate pain control as well 
as on ocular discomfort/soreness that can often follow IVI. Additionally, we plan to have 
two intervention groups that look compared Bromfenac 0.09% instillation 30 minutes 
prior to IVI and instillation immediately following IVI.  
 
The primary goal of this study is to determine if topically administered Bromfenac 0.09% 
eye drops can reduce the discomfort that patient experience both during and after 
intravitreal injections. Additionally, we will investigate the effect of both pre and post 
injection application of topical Bromfenac 0.09% on subjective pain scores.  
 
Our study will be a pilot study consisting of 45 patients. These patients will be selected 
from those that have a diagnosis requiring intravitreal injection of an anti-VEGF agent. 
From these patients we will select those that have already undergone intravitreal 
injection at least once before. This will serve to minimize bias from initial injection 
anxiety and will give patients a comparative data point (prior injection discomfort). 
Patients will be randomized into one of three groups, which will be known as group A, B 
or C. The groups will have drop regimens as follows: 
 
Group A: Will receive 1 drop of topical Bromfenac 0.09% 30 minutes prior to the 
injection and then 1 drop of an artificial tear eye drop immediately after the injection and 
wash.  
 
Group B: Will received 1 drop of an artificial tear eye drop 30 minutes prior to the 
injection and then 1 drop of topical Bromfenac 0.09% immediately after the injection and 
wash. 
 

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Group C: Will received 1 drop of an artificial tear eye drop 30 minutes prior to the 
injection and then 1 drop of an artificial tear eye drop immediately after the injection and 
wash. 
 
All labels will be removed from the bottles and the patients will be blinded to which 
group they belong to. The treating physicians (Dr. Mititelu and Dr. Chang) will also be 
blinded to which group the patients belong to.  
 
Immediately following the injection, each patient will be asked to rate their pain using 
the Wong-Baker FACES pain scale as well as the McGill Pain Questionarire (SF-MPQ). 
Patients will then be given instructions and will be told to expect a call at 6 and 24 hours 
regarding further follow up phone questionnaires. Patients will also be provided with a 
phone number to contact should they have any complications (ie. discomfort, increased 
pain, vision changes, or any other questions). Patients will be provided with a copy of 
the Wong-Baker FACES pain scale and the McGill Pain Questionnaire to take home 
with them. Patients will be called 6 hours post-injection for further assessment of their 
pain using both the Wong-Baker FACES pain scale and the McGill Pain Questionnaire 
(SF-MPQ). At 24 hours, patients will again be contacted and their pain will be assessed 
one final time using both the Wong-Baker FACES pain scale and the McGill Pain 
Questionnaire (SF-MPQ). This will serve as the last point of data gathered for our study 
for our patients. They will continue regular follow up with their ophthalmologist as 
scheduled.  
 
 
Background and Significance 
Intravitreal injections (IVI) are a common form of treatment for multiple retinal 
pathologies. They are rapidly becoming one of the most common forms of treatment 
performed in the field of ophthalmology and have often improved visual outcomes for 
patients. Despite the massive benefit. the downside is that patients often require 
multiple repeat injections to maintain control of their disease state. Many patients fear 
injections due to the anxiety and pain during the injection and the experience discomfort 
after the procedure.1,2 
 
Multiple strategies have been attempted to reduce the discomfort that patients 
experience. One of the most common being topical proparcaine and lidocaine gel. This 
can provide some immediately relief, but often does little to control pain that some 
patients experience hours after the injection.2,3 Increased lidocaine concentration has 
been applied to the eye with cotton-swaps and has provided adequate analgesia during 
the injection, but patients often still experienced pain hours afterwards.2 Despite the use 
of different concentrations of lidocaine and various types of topical eye drops 
(tetracaine, epinephrine with cocaine, proparacaine) little relief was provided many 
hours post injection.4,5,6 
 
To rate the pain immediately following injections, studies have utilized the Wong-Baker 
FACES pain scale. This scale proved to be an effective measure of subjective pain in 
patients and allowed studies to adequately compare pain scores across treatments 

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(topical anesthesia drops, gel, lidocaine-soaked cotton swabs) versus control groups. It 
must be mentioned that this scale is only accurate and useful if patients are able to 
understand the pain scale and to properly rate what they are experiencing. This scale is 
particularly useful in elderly patients as it is very visual in nature.5,6 
 
Topical non-steroidal anti-inflammatory drugs (NSAIDs) have been looked at as a 
method of controlling immediate and post injection pain. Diclofenac, Nepafenac 0.1% 
and Bromfenac 0.9% has been shown to be an effective method of controlling post 
injection pain up to 6 hours after intravitreal injection.8,9,10 Diclofenac has also been 
utilized in patients with diabetic retinopathy prior to undergoing pan-retinal 
photocoagulation (PRP) and was found to be effective at reducing the discomfort 
experienced.9 All theNSAIDs mentioned above showed improvement in pain, mainly at 
6 hours post injection.  
 
To evaluate the pain experienced hours after injection, the short form McGill pain 
assessment questionnaire (SF-MPQ) was utilized.12 Given it measures not only the 
level of pain, but also the type of pain that the patient is experiencing, the SF-MPQ 
proved to be an effective and comprehensive way to quantify and qualify the discomfort 
of the patient after IVI. Studies showed that by using this scale a statistically significant 
reduction in post injection pain was reported with topical NSAIDs.  
 
The McGill pain assessment questionnaire has also been utilized in patient with severe 
dry eye. It proved effective as an easy to use questionnaire for patients to report pain 
and allowed the study to obtain statistically significant results.11 
 
All studies we have reviewed assess pain immediately after and then again at 6 hours 
after injection. However, the studies did not report any findings or data points at 24 
hours post injection. We will look at the use of the topical drop Bromfenac 0.09%, which 
has shown reduction in post injection pain.10 We will evaluate Bromfenac 0.09% effect 
on pain if given 30 minutes pre-injection or immediately post injection. Surveys will be 
completed immediately after injection, 6 hours post-injection, and 24 hours post-
injection.  
 
Risks associated Bromfenac are minimal, and in clinical trials done by the manufacturer, 
mainly consisted of surface irritation. Some patients did report headaches and 
increased eye redness; however these symptoms were described only in 2-7% of 
patients. More severe complications such as corneal thinning and erosions were 
reported in the post-marketing surveillance group and were more associated with 
chronic use.13 A study performed by Georgakopoulos et al looked at Bromfenac 0.09% 
in preventing and decreasing post-injection pain. Of the 65 patients enrolled in that 
study, none had any adverse reactions to the topical Bromfenac 0.09%.10 
 
Specific Aims/Study Objectives 
 
Hypothesis and Purpose 

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Our hypothesis is that intervention with a topical NSAID will alleviate pain experienced 
at intravitreal injection (IVI) and post-IVI. We will assess the effectiveness of topical 
Bromfenac 0.09% on pain after IVI. In addition, we will investigate whether pre or post 
injection instillation of topical Bromfenac 0.09% has a greater effect on post-injection 
pain. 
 
Duration 
The study will last 1 day (24 hours) total for each subject. We plan to enroll patients that 
require an intravitreal injection of an anti-VEGF medication for their eye disease. We 
plan to enroll 45 patients for this pilot study. The data analysis will be performed at the 
end of the study. It is expected that the study will be completed, and the results will be 
available within 1 year from time of commencement. 
 
Outcome measures 
1. Assessment of topical 0.09% Bromfenac’s analgesic effect pre- and post-injection in 
patients undergoing intravitreal injections of anti-VEGFs as measured by the McGill 
Pain Questionnaire (SF-MPQ). (Time Frame: 6 hours and 24 hours after IVI) 
2. Assessment of topical 0.09% Bromfenac’s analgesic effect pre- and post-injection in 
patients undergoing intravitreal injections of anti-VEGFs as measured by the Wong-
Baker FACES pain scale. (Time Frame: immediately following IVI) 
 
Research Design and Methods 
 
Recruitment and Location 
Subjects are patients with a retinal disease requiring anti-VEGF therapy who are under 
the care of Dr. Mihai Mititelu and other retinal specialists at the University of Wisconsin 
Hospital and Clinics (UWHC). Ophthalmologists involved in the patients’ clinical care will 
be the first to approach patients about the study. For patients who are interested and 
meet the criteria, the study team will explain the study, guide the patient through the 
study specific consent form, and answer subject questions. 
 
Subjects 
 
Subject population 
The study population will consist of 45 eyes of patients recruited by ophthalmologists at 
UWHC. 
• Inclusion criteria 
o Age ≥ 18 years 
o Eyes with retinal pathology requiring anti-VEGF therapy that have 
previously had an IVI 
• Exclusion criteria 
o History of previous eye surgery other than cataract extraction 
o Herpetic eye disease 
o Uncontrolled glaucoma 
o Uveitis 
o Acute conjunctivitis 

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o Patients less than 18 years of age 
o Pregnancy 
o Known previous adverse response or contraindication to intravitreal 
injection, Bromfenac, or other NSAIDs. 
o Keratitis including povidone-induced keratitis 
o Bullous keratopathy 
o Diagnosis of dry eye syndrome 
o Uncontrolled diabetes 
o NSAID use 3 days prior to IVI 
 
Consent procedures 
 
Only patients who require anti-VEGF therapy will be assessed by the treating physician 
for eligibility for the study. For the patients who qualify for the study, the study team will 
explain the study to them, including the risks. The subjects will have the opportunity to 
ask questions. Patients who agree will then be asked to sign the consent form. They will 
receive a copy of the consent form. Women of childbearing age who are unsure of their 
pregnancy status will be excluded from the study unless they first undergo a pregnancy 
test.  
 
Research Design 
 
1. This is a prospective pilot study of approximately 45 eyes with retinal pathology 
requiring anti-VEGF therapy.  
 
2. Patients identified as candidates who express interest in participating will sign a 
consent form and will clinically undergo standard care IVI and randomly placed in one of 
three groups: Group A, B or C. Each group will consist of 15 patients. 
 
 
a. Standard of care IVI entails first anesthetizing the eye with topical numbing 
eye drops and then cleansing the ocular surface and eyelids with a betadine cleaning 
solution. A lid speculum will then be placed in order to keep the ocular surface free form 
lashes and to minimize interference from the eyelids during the injection. Once these 
steps have been completed the appropriate injection of an anti-VEGF agent will be 
administered. The lid speculum will then be removed. The patient’s eye will then be 
cleansed of any remaining betadine eye wash solution.  
 
3. Group Explanations (Patients will not be aware of what group they belong to via 
removal of any labels on the bottles): 
 
- Group A: Will received 1 drop of topical Bromfenac 0.09% 22 minutes prior to 
the injection and then 1 drop of an artificial tear eye drop immediately after the injection 
and wash.  
 
- Group B: Will received 1 drop of an artificial tear eye drop 22 minutes prior to 
the injection and then 1 drop of topical Bromfenac 0.09% immediately after the injection 
and wash. 

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- Group C: Will received 1 drop of an artificial tear eye drop 22 minutes prior to 
the injection and then 1 drop of an artificial tear eye drop immediately after the injection 
and wash. 
 
4. All patients involved in the study will be assessed for subjective pain score 
immediately (1 minute) following IVI using the Wong-Baker FACES pain scale and the 
McGill Pain Questionaire (SF-MPQ). This result will be recorded. 
 
5. Subjects will be contacted at home at their preferred contact number at 6 hours post 
injection for further assessment of their level of pain. This will be assessed by using 
both the Wong-Baker FACES pain scale and the McGill Pain Questionnaire (SF-MPQ). 
Results will then be recorded. 
 
6. Subjects will be contact the following day (24 hours post-injection) at home at their 
preferred contact number at 24 hours post injection for assessment of the pain level 
again both the Wong-Baker FACES pain scale and the the McGill Pain Questionnaire 
(SF-MPQ).  
 
7. No further follow up appointment will have recorded data and patients will follow up 
with their normal provider as scheduled.  
 
Intravitreal injection Procedure 
Group A: Topical Bromfenace prior to intravitreal injection and artificial tears 
immediately following intravitreal injection 
Group B: Artificial tears prior to injection and topical Bromfenac immediately following 
intravitreal injection 
Group C: Artificial tears prior to and following intravitreal injection 
Injections procedure will then proceed as follows:  
Preparations for the injection will then be made first by tilting the patient back in the 
exam chair. The eye that is to be injected will be marked by placing a sticker on the 
patient’s forehead above the indicated eye. Depending on the group 1 drop of artificial 
tears (Groups B and C) or Bromfenac (Group A) will be instilled in the eye intended for 
injection. After instillation of the first drop a timer will be set for 10 minutes. After 10 
minutes has elapsed, a drop of topical tetracaine 0.5% will be instilled. A timer will then 
be set for 5 minutes. After 5 minutes have elapsed, the eye will cleansed with betadine 
5% solution by instilling 2 drops of betadine in the eye. A timer will be set for 2 minutes. 

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After 2 minutes have elapsed topical lidocaine (Akten) gel 3.5% will be instilled in the 
eye marked for injection. A timer will then be set for 5 minutes. After 5 minutes, the 
physician will come into the room for the intravitreal injection and will proceed with 
injection of Avastin in the superotemporal quadrant of the eye after placing a eyelid 
speculum to hold the lids open. The treating physician will be masked as to what group 
the patient has been placed in. After the injection has taken place, 1-2 fingers will be 
held up and the patient will be asked how many they see. This step is done to assess 
no visual changes following intravitreal injection. The eyelid speculum will then be 
removed.  After this is done the patient’s eye will then be rinsed with an eyewash 
cleansing solution to remove any excess betadine. After thorough cleansing with the 
eye wash. The treating physician will then leave the room. The Wong-Baker and SF-
MPQ pain questionnaires will then be administered by a trained study member. The 
patient, depending on what group they belong to will then be given one final eye drop. It 
will be either artificial tears (Groups A and C) or Bromfenac (Group B). The patient will 
then be told to expect a call 6 hours and 24 hours later. They will be given a paper copy 
of both the Wong-Baker and McGill Pain Questionnaires. They will be told to keep these 
easily accessible as these will be utilized during their 2 phone follow up calls. The 
patient will then leave the clinic.  
Of note all physicians involved in providing intravitreal injections are Retina fellowship 
trained and use the same injection protocol, including choice of anesthesia, type of 
medication/needle/syringe, location of actual injection, etc. Injections will be given in the 
same location (for ex. Superotemporal quadrant as above) to ensure consistency, while 
not deviating from standard of care in which this location is commonly used by retina 
practitioners for intravitreal injection. This ensures that there will be minimal variation in 
the overall injection experience.  
The patient’s care will not differ from standard of care if they decide to participate in this 
study.   
Being involved in the study group may prolong the patient’s overall visit length by 
approximately 20-30 minutes. This time would include enrollment in the study, consent, 
group placement, as well as choice and use of numbing agent. These additional 
activities would not interfere in any manner with standard of care activities, specifically 
topical anesthesia followed by intravitreal injection using sterile technique. 
 
Data and Safety Monitoring Plan 
 

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Risk Identification and Minimization 
The risk that patients involved in this study will be exposed to will be instillation of 
topical Bromfenac 0.09%, a non-steroidal anti-inflammatory drug (NSAID) drop. The 
drop will be administered via a single use bottle of the medication and the same bottle 
will not be used on multiple subjects to minimize risk of cross-contamination. 
 
Patient’s will also be given an intravitreal injection of an anti-VEGF agent, but this will 
not be a change from what their appointment would normally entail.  All of our study 
patients will be those whom would normally undergo an injection for their diagnosis 
regardless of their inclusion/exclusion from the study. 
 
Bromfenac 0.09% is an NSAID drop and has been shown to be relatively safe in 
patients. This is especially true for our method of using this medication as it will only be 
applied topically. With that being side it does have a side effect profile which includes, 
foreign body sensation in the eye, conjunctival hyperemia, eye irritation, eye discomfort, 
eye pruritus, eye redness, headache, and rarely iritis. The manufacturer of this drop 
reports these events to have occurred in 2-7% of their patients during clinical trials. 
Post-marketing surveillance has led to less common, but still possible side effects which 
included corneal erosions, corneal perforation, corneal thinning, and epithelial 
breakdown in some patients. These are typically associated with chronic, frequent use. 
 
It should be noted that any of patient who has previously has a poor interaction with any 
type of NSAID drop will not be included in our study. 
 
Patient will be assessed immediately following their intravitreal injection for their 
subjective pain scores using the Wong-Baker FACES pain scale. They will also be 
provided a number to call should they have any questions of eye irrigation post 
injection. All of the patient’s in our study will have previously had intravitreal injections 
so they will be already familiar with the process.  
 
To minimize risks, only experienced professionals will administer the medication. All 
subjects will be monitored closely for any adverse reaction and treated appropriately if 
any of these would develop. If any adverse reactions do occur, the principle investigator 
will be notified and appropriate action will be taken to assist and treat the patient 
appropriately.  
 
Patients will be contact at 6 hours and 24 hours post injection for subjective pain scores 
using the McGill Pain Questionaire (SF-MPQ). During this telephone encounter patients 
will also have the opportunity to ask any questions or report any symptoms that they 
may be experiencing.  
 
Data and Safety Monitoring Procedures 
Data collected will be monitored by the Clinic Eye Research Unit (CERU) team listed on 
this protocol.   
 

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Data will be assessed first after the first 7 subjects in each group have been enrolled 
and then again after the final 8 subjects in each group have been enrolled. 
 
Unanticipated problems, adverse events, protocol deviations, and protocol violations will 
be reported as soon as they are discovered and will be recorded.  
 
The study will be stopped if more than 30% of our subjects have an unanticipated 
adverse reaction to the medical indicating an issue with the medication. The study will 
also be stopped if any breach in confidentiality is detected. 
 
Potential risks 
 
The potential risks related to study participation include: 
1. Drug reaction to topical Bromfenac 0.09% which includes, increase in IOP, foreign 
body sensation in the eye, eye pruritus, eye redness, headache, conjunctival 
hyperemia, eye irritation, eye discomfort, and rarely iritis. Also have a small risk of 
corneal erosions, corneal thinning, corneal perforation, and epithelial breakdown.  
2. Increased inflammation and endophthalmitis from the intravitreal injections. Although 
extremely rare, it is possible to have an increase in inflammation and even 
endophthalmitis from an intravitreal injection.  
3. Large, controlled trials and meta-analyses have been done looking at adverse 
events from intravitreal Anti-VEGF agents. These have shown that “anti-VEGF 
monoclonal antibodies did not significantly increase overall mortality, cardiovascular 
mortality, stroke, myocardial infarction, VTEs, or hypertension.   
4. Confidentiality breach. 
Protection of subjects 
 
Subjects will be examined at a standard of care appointment. For those that enroll into 
the pilot study, their pain (post IVI) will be assessed at the conclusion of the 
appointment. Subjects will be phoned 6 and 24 hours after the IVI to assess pain level. 
All complications will be recorded. Patients will be instructed to call immediately for an 
appointment if they notice any standard care risks such as a change in the vision, 
appearance of the eye, or development of pain in the eye. They will be provided with a 
24/7 contact number should they have any difficulties. Data collection forms will include 
the study identification number; no names will be used in the forms. Presentations and 
publications will not identify individual patients.  
Statistical Considerations 
Our study is a pilot study and will include a total of 45 patients. We will evaluate 3 
different groups and each group will consist of 15 patients.  
 
For Outcome 1, correlative studies of pain relief do not exist after IVI. Therefore, a 
power calculation cannot be extrapolated. Outcome 1 is written as a pilot experiment to 

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gather data for interim analysis. If statistical significance is not achieved at the interim 
analysis, the data will provide us with the deviation required to calculate the number of 
subjects needed for further recruitment in an expanded study.  
 
For Outcome 2, based on initial calculations to achieve a power of 80% and a standard 
deviation of 1.8 gathered from the literature, 14 subjects in each group will be needed.3 
We plan to use 15 subjects per group to ensure statistical significance is achieved. We 
will not re-use these subjects in future studies.  
 
Data and Record Keeping 
Research intervention will be conducted in a private room; collection of sensitive 
information about subjects will be limited to the amount necessary to achieve the aims 
of the research. Data collection forms will include the study identification number; no 
names will be used in the forms. Presentations and publications will not identify 
individual patients.  
All paper data will be stored in locked cabinets. All the electronic data will be stored in 
UW IT approved password-protected computers and/or UW IT approved devices. This 
will be kept at UWHC sites in a room with number lock available only to individuals 
listed in study protocol. The confidentiality of records will be maintained in accordance 
with applicable state and federal laws. All the identifiers and information in paper format 
will be shredded. The electronic data that includes any patient identifiers will be deleted 
at the conclusion of the study. Raw data including information regarding injection 
comfort level will be kept to aide in future studies.  
Bibliography & References Cited 
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With and Without Subconjunctival Lidocaine Injection for Intravitreal Injection: A 
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310. DOI:10.3928/23258160-20140709-06  
 
2. Ninel Z Gregori, Matthew J Weiss, Raquel Goldhardt, Joyce C Schiffman, 
Edgardo Vega, Cherrie-Ann Mattis, Wei Shi, Linda Kelley, Vilma Hernandez & 
William J Feuer (2012) Randomized clinical trial of two anesthetic techniques for 
intravitreal injections: 4% liquid lidocaine on cotton swabs versus 3.5% lidocaine 
gel, Expert Opinion on Drug Delivery, 9:7, 735-741, 
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3. Knecht PB, Michels S, Sturm V, Bosch MM, Menke MN. Tunnelled Versus 
Straight Intravitreal Injection: Intraocular Pressure Changes, Vitreous Reflux, and 
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4. Ornek N, Apan A, Ornek K, Gunay F. Anesthetic effectiveness of topical 
levobupivacaine 0.75% versus topical proparacaine 0.5% for intravitreal 

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7. Rifkin L, Schaal S. Shortening ocular pain duration following intravitreal 
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8. Makri O, Tsapardoni F, Plotas P, Aretha D, Georgakopoulos C. Analgesic Effect 
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