Abstract
Purpose:
To test the safety and preliminary efficacy of rapid, non-pharmacologic anesthesia via cooling for intravitreal injections.
Design:
Single center, randomized, phase 1 dose-ranging safety study (NCT 02872012)
Subjects:
Adult subjects ≥ 18 years of age with a diagnosis of exudative macular degeneration or diabetic macular edema in both eyes requiring bilateral anti-VEGF therapy were included.
Methods:
A handheld device was developed to provide anesthesia via cooling to a focal area on the surface of the eye immediately prior to intravitreal treatment (IVT). In 22 subjects undergoing bilateral IVT, one eye was randomized to receive standard of care (SOC) lidocaine-based anesthesia and the other eye received cooling-anesthesia at one of 5 different temperatures and cooling times. Subjective pain was assessed via the visual analog scale (VAS, 1–10) at 2 timepoints: (1) immediately following IVT, and (2) 4 hours post-IVT. Treated eyes were assessed for ocular safety via biomicroscopic examination performed 24-hours post-IVT.
Main Outcome Measures:
We determined the occurrence of adverse events in eyes treated with cooling anesthesia. Mean VAS pain scores immediately post-IVT and 4-hours post-IVT in eyes receiving cooling anesthesia were compared to eyes receiving SOC.
Results:
A total of 44 eyes were treated, 22 with cooling anesthesia and 22 with lidocaine-based anesthesia. There was no dose-related toxicity with the application of cooling anesthesia. Mild, transient adverse events were recorded in 32% of subjects treated with cooling anesthesia versus 44% of subjects receiving SOC. VAS pain scores immediately following intravitreal injection were 2.3 ± 0.4 for subjects receiving SOC and 2.2 ± 0.6 in subjects receiving −10°C cooling anesthesia (P = 0.8, mean ± SEM). Four hour post-injection pain scores were 1.6 ± 0.4 for SOC and 1.2 ± 0.5 in the combined −10°C treatment arms (P = 0.56, mean ± SEM).Total procedure time, including anesthesia and injection, was 124 ± 5 seconds for subjects treated with cooling anesthesia versus 395 ± 40 seconds for the SOC groups (P < 0.0001).
Conclusions:
Ultra-rapid cooling of the eye for anesthesia was well tolerated, with −10°C treatment resulting in comparable levels of anesthesia to SOC with a statistically significant reduction in total procedure time.
Precis:
We are reporting the positive phase 1 results of ultra-rapid cooling as a method to anesthetize the eye prior to intravitreal injection. This pilot study demonstrated that focal ocular cooling is safe and well-tolerated.
Intravitreal anti-VEGF therapy has transformed the treatment landscape of exudative macular degeneration, diabetic macular edema, retinal vein occlusion, and other forms of exudative maculopathy. Multiple studies have shown that anti-VEGF not only prevents vision loss, but also results in visual acuity gains of 15 letters or more in 25–41% of treated patients.1–5 The success of this therapy has revolutionized the field of retina and saved vision for hundreds of thousands of patients, simultaneously making intravitreal injection the most common procedure performed by retina specialists and among the most common in all of medicine. Along with this great success has come a significant burden on patients and the health care system. Based on a conservative estimate, over 6 million intravitreal injections were given in 2016 in the United States alone,6 and this number continues to increase due to the aging population, expanding indications for anti-VEGF therapy, and the obesity and diabetes epidemics.
Despite receiving local anesthesia prior to the procedure, most patients report at least mild pain at the time of their intravitreal injection.7–10 This is of particular importance because injection pain and the fear of injections can lead to missed treatments. In a cohort of 314 patients, Polat and colleagues found injection pain and fear of injections to be the leading cause for treatment non-compliance.11
Lidocaine-based topical ocular anesthesia is the standard of care (SOC) for intravitreal treatment (IVT) around the world.12 Since lidocaine must diffuse through ocular tissues to block nerve conduction, it takes several minutes to provide adequate anesthesia. The time required to achieve adequate anesthesia lengthens patients’ visit times and can affect clinical workflow, resulting in inefficiencies, further compounding the problem. Despite the limitations of lidocaine-based anesthesia for IVT, there have been minimal improvements in ocular anesthesia since ranibizumab was first approved by the FDA in 2006 to treat exudative age-related macular degeneration (AMD). The lack of improvement in ocular anesthesia options is particularly noteworthy given the dramatic growth in IVT volume since 2006.
There is no consensus on the optimal type of lidocaine-based anesthesia, a fact that is highlighted by the nearly even split of utilization by retina specialists. The 2019 ASRS practices and trends survey of 1,004 retina specialists found that 22.5% of US retina specialists use anesthetic eyedrops, 25.0% use topical anesthetic gel, 17.9% use topical anesthetic applied with a pledget, and 33.4% use subconjunctival lidocaine.12 A survey of IVT practice patterns found that despite the fact that 87% of retina specialists claim that patient comfort is one of their primary considerations when selecting ocular anesthesia, 74% of retina specialists report having patients request a different form of anesthesia.13 Taken together, these data suggest that optimal ocular anesthesia represents an unmet need in the intravitreal drug delivery space.
The analgesic effect of cold temperatures has been known for centuries, with Hippocrates (460–377 BC) writing of the use of ice and snow packs as a local pain reliever before surgery.14, 15 Transient nerve conduction blockade is achieved at 0°C, with longer-lasting anesthesia achieved at temperatures between −5°C and −20°C.14 One of the distinct benefits of cooling-based anesthesia is the rapid onset of action, with a nearly simultaneous anesthetic effect occurring with the decrease in nerve temperature. While tissue-destructive cryotherapy at temperatures below −50°C is widely used as a treatment for tumors and retinal tears, cooling tissue at higher temperatures for anesthesia has not been thoroughly evaluated. In light of the need for safe, rapid ocular anesthesia prior to IVT, our team developed a portable device to deliver rapid, focal cooling to the ocular tissue to provide anesthesia for intravitreal injection. A pre-clinical, in vivo study demonstrated no signs of toxicity in rabbits treated at temperatures as low as −30°C for 30 seconds.16 Based on this safety data, the device was advanced to a first-in-human study (clinicaltrials.gov: NCT02872012). The goal of this phase 1 trial was to evaluate the safety and feasibility of a focal cooling device for use prior to IVT.
Methods
This single center, randomized, controlled clinical trial adhered to the tenets of the Declaration of Helsinki17 and was approved by the University of Michigan Institutional Review Board (IRB). Study participants provided written informed consent, and a data and safety monitoring committee provided oversight (clinicaltrials.gov: NCT02872012).
Study Overview
The study was carried out in subjects receiving bilateral anti-VEGF injections for exudative macular degeneration or diabetic macular edema (DME). Key inclusion criteria included age ≥ 18 years, having received at least one prior injection in both eyes within 90 days of study enrollment, and the ability to give informed consent. Subjects were excluded if they were allergic to lidocaine, were unable to comply with the study protocol, or were diagnosed with any pre-existing conjunctival, episcleral, or scleral defects or disease.
The study design is summarized in Figure 1. One eye of each subject received SOC lidocaine-based anesthesia consisting of either lidocaine-soaked pledgets or FDA-approved 3.5% lidocaine gel (Akten, Akorn, Lake Forest, Illinois). The second eye received anesthesia via cooling. Subjects’ first eyes were randomized to receive either SOC or cooling anesthesia. The eye receiving cooling anesthesia was further randomized to receive 1 of 5 different cooling arms as summarized in Figure 1. SOC and cooling treatments were performed on separate days. Due to the differences in the SOC vs cooling application, there was no masking employed for subjects or the treating physician. The treating physician was informed of the random assignment immediately prior to the procedure by a study coordinator. Focal ocular cooling was applied using a portable, battery powered, rechargeable, thermoelectric cooling device. The device was programmed to enable the user to select a variety of cooling temperatures. Real-time control prevented excess cooling, and a built-in timer allowed for precise control of exposure to cooling. The device had a user interface that included a screen to display device temperature and the cooling timer, enabling the physician user to accurately monitor treatment parameters. The device underwent extensive benchtop testing to demonstrate the accuracy and reproducibility of temperature readings. A disposable, sanitized, single-use tip contacted the eye, and two small protrusions on the tip left temporary indentations on the surface of the eye to guide placement of the intravitreal needle.
Figure 1. Phase 1 Study Design.
Standard of Care: Lidocaine-based anesthesia; Examination: Biomicroscopic examination; Telephone call: telephone-based follow-up
Injection Procedure: SOC anesthesia arms
A single drop of proparacaine was placed in the eye at the start of the procedure. Eyes received either 3 sets of cotton tipped pledgets soaked in 4% lidocaine for approximately 1–2 minutes for each set, or application of 3.5% lidocaine gel to the ocular surface for a minimum of 3 minutes prior to treatment. Following completion of numbing, the eyelids were swabbed with betadine, an eyelid speculum was placed, and betadine was applied to the conjunctival injection site for 15 seconds. The physician used a caliper to measure 3 or 4 mm from the limbus of the eye. Another drop of betadine was placed over this spot for 15 seconds and the injection was administered.
Injection Procedure: Cooling anesthesia arms
A drop of proparacaine was placed in the eye receiving cooling anesthesia and the lids were swabbed with betadine. The physician placed a lid speculum in the patient’s eye and a drop of betadine was applied at the site of treatment. A minimum of 15 seconds elapsed prior to application of cooling. During this 15–20 second interval, the physician verified that the correct temperature and time of cooling were selected based on the subject’s assigned arm in the trial, and then activated the ultra-rapid cooling device to enable the tip to reach the required temperature. Immediately prior to placing the device tip against the eye, the physician pressed the activation switch, after which the device was applied to the surface of the eye. A timer sounded to indicate completion of cooling and safe removal from the surface of the eye. The device was then withdrawn, leaving 2 marks on the ocular surface at 3 and 4 mm from the limbus to guide needle placement. Immediately before giving the injection, the physician placed a second drop of betadine on the surface of the eye at the site marked for the injection and waited an additional 15 seconds. The physician then administered the intravitreal injection (animation; supplemental file, available at http://www.aaojournal.org/).
Safety and efficacy assessment
Immediately following the injection, subjects were asked to report their injection pain based on the visual analog pain scale (VAS, 1–10). All subjects underwent a biomicroscopic examination before treatment and again within 30 minutes of completing treatment. A follow-up biomicroscopic examination was performed 24 hours post-treatment. Subjects received a phone call from a study coordinator 4-hours post treatment to record subjective post-IVT pain (assessed using the VAS pain scale) and again at day 7 to record any delayed side effects of treatment.
The primary outcome measure was subject-reported pain at the time of the injection, measured using the VAS. Secondary outcomes included subject-reported post-injection pain and discomfort reported 4-hours post-injection and patient-reported adverse events 7 days post-injection. Physician-graded ocular side effects were recorded within 30 minutes of administration of the intravitreal injection and again 24 hours following the injection. Ocular side effects measured included subconjunctival hemorrhage (SCH), conjunctival hyperemia, conjunctival injection, and corneal keratopathy. The following grading scale was used: 1. No ocular side effects; 2. mild ocular side effects (SCH involving less than 25% of the ocular surface, trace to 1+ conjunctival hyperemia, trace to 1+ conjunctival injection, or trace to 1+ corneal keratopathy); 3. Marked ocular side effects (SCH involving at least 25% of the ocular surface, 2–4+ conjunctival hyperemia, 2–4+ conjunctival injection, or 2–4+ corneal keratopathy). In addition, each eye was assessed for other signs of anterior segment toxicity, including anterior chamber reaction and hypotony. Significant adverse events included any form of ocular toxicity resulting in permanent loss of vision. The time for the entire injection procedure, from application of proparacaine through removal of the eyelid speculum, was recorded for each patient.
Statistical analysis
This was a Phase 1 trial to establish safety and feasibility, and no formal sample size calculation was performed. We estimated that inclusion of 44 eyes was sufficient to determine the safety and tolerability of the intervention. Results were tabulated and the data were analyzed using GraphPad Prism software (version 8.1.1, San Diego, CA). Comparison of means between eyes were made using paired t-tests. Means are reported with standard error of the mean (SEM) and range, and a p-value < 0.05 was considered statistically significant.
Results
A total of 23 patients were enrolled in the study and 44 eyes of 22 patients were randomized with cooling anesthesia or SOC (Table 1). One subject withdrew voluntarily prior to study intervention. The mean age of randomized subjects was 77 years (standard deviation (SD): 11, range: 56–89). Six subjects were male (27%) and 16 were female (73%). The mean number of previous injections was 29 (SD: 28, range: 4–111). Fourteen subjects (64%) received aflibercept, and 8 (36%) received bevacizumab. Eleven subjects (50%) were diagnosed with exudative AMD and 11 (50%) were diagnosed with DME.
Table 1.
Demographics and baseline characteristics of patients in Phase 1 study of cooling anesthesia for IVT
| Feature | Number (n=22) |
|---|---|
| Age, years | |
| Mean (SD, range) | 71 (11, 56–89 years) |
| Sex, number (%) | |
| Male | 6 (27) |
| Female | 16 (73) |
| Number of previous injections | |
| Mean (SD, range) | 29 (28,4 – 111) |
| Anti-VEGF agent, number (%) | |
| Bevacizumab | 8 (36) |
| Diagnosis, number (%) | |
| Exudative AMD | 11 (50) |
| DME | 11 (50) |
Safety
At 24-hours post IVT, thirteen (68%) of the eyes receiving cooling anesthesia had no ocular side effects, and 6 (32%) had mild ocular side effects (Table 2). In the SOC group, ten (56%) of the eyes had no ocular side effects, and 8 (44%) had mild side effects. Three subjects in the cooling treatment groups and 4 subjects in the SOC group did not present for the 24-hour follow up visit. There were no significant adverse events, and no eyes in either group had marked ocular side effects. There was no clinical evidence of post-cooling toxicity in any eye receiving cooling, no serious transient adverse events, no unexpected adverse events, no discomfort with cooling anesthesia, and no difficulty with the device on the eye for up to 20 seconds. Day 7 post-treatment call data were obtained in 14/22 eyes in the SOC group and 16/22 in the cooling groups, and there were no adverse events in either group.
Table 2:
Treatment-related adverse events in subjects in the focal cooling and standard of care (SOC) groups
| Ocular Findings | Number (%) |
|---|---|
| No ocular side effects | |
| SOC | 10 (56) |
| Mild side effects | |
| SOC | 8 (44) |
| Marked side effect | |
| SOC | 0 |
|
|
Preliminary Efficacy
Injection pain showed a dose response trend with cooling anesthesia. Eyes treated with colder temperatures and longer time points of cooling tended to exhibit better pain control (Figure 2A). The mean VAS pain score in cooling anesthesia groups was as follows: Group 1 (−5°C for 10 seconds) 7.0 ± 1.5; Group 2 (−5°C for 20 seconds) 3.1 ± 0.6; Group 3 (−7°C for 20 seconds) 3.0 ± 1.1; Group 4 (−10°C for 10 seconds) 1.8 ± 0.8; and Group 5 (−10°C for 20 seconds) 2.4 ± 0.8 (mean ± SEM). The mean VAS pain score in SOC anesthesia groups was as follows: Group 1, 2.3 ± 0.9; Group 2, 2.7±0.6; Group 3, 2.8 ± 0.8; Group 4, 0.8 ± 0.6; and Group 5, 2.4 ± 1.5. Cooling anesthesia showed IVT injection pain control that was similar to SOC in Groups 2–5 (P=0.3 to >0.9, paired t-test, Figure 2). A mean difference of 4.7 ± 1.8 (mean ± SEM) for IVT injection pain between SOC and cooling anesthesia in Group 1 was the largest of all groups but this difference did not reach statistical significance (P=0.1, paired t-test)
Figure 2: Pain scores for intravitreal injection.
A) Comparison of Visual Analog Scale (VAS) pain scores between cooling anesthesia groups and Standard of Care (SOC) lidocaine-based anesthesia reported immediately post-injection. SOC eyes are grouped with the fellow eyes randomized to each cooling dose group. B) Comparison of VAS pain scores between cooling anesthesia and SOC lidocaine-based anesthesia reported 4 hours post injection. SOC eyes are grouped with the fellow eyes randomized to each cooling dose group. C) Post-injection pain score comparison between combined SOC arms and Group 5 (−10°C for 20 seconds). Mean ± SEM, P=0.02, Welch’s t-test.
Post-injection pain scores measured 4 hours after IVT were similar between SOC and cooling anesthesia within each group (P=0.3 to 0.8, paired t-test, Figure 2B). The mean VAS post-IVT pain score in cooling anesthesia groups was as follows: Group 1, 3.3 ± 2.4; Group 2, 1.4 ± 0.7; Group 3, 2.8 ± 1.1; Group 4, 2.4 ± 1.1; and Group 5, 0.4 ± 0.3 (mean ± SEM). The mean VAS pain score in SOC anesthesia groups was as follows: Group 1, 2.0 ± 1.5; Group 2, 1.6 ± 0.9; Group 3, 1.5 ± 1.0; Group 4, 2.0 ± 0.6; and Group 5, 1.2 ± 0.6. Post-injection pain score in Group 5 (receiving cooling anesthesia at −10°C for 20 seconds) was the lowest of all groups. VAS post-injection pain difference between combined SOC arms (n=22) and Group 5 (n=5) was 1.2 ± 0.5 (mean ± SEM), which was statistically significant (P=0.02, Welch’s t-test, Figure 2C).
The mean IVT time for eyes treated with SOC was 395 seconds ± 40 seconds compared to 124 ± 5 seconds for eyes treated with cooling anesthesia (p < 0.0001, mean ± SEM, paired t-test, Figure 3).
Figure 3: Intravitreal injection procedure time.
Comparison of procedure time between cooling anesthesia groups and Standard of Care (SOC) lidocaine-based anesthesia. Mean ± SEM, P<0.0001, paired t-test.
Discussion
Despite the transformative nature of intravitreal anti-VEGF treatment, receiving IVT continues to be a source of pain and anxiety for patients.18 The dramatic growth in the need for and use of IVT has placed significant strains on clinical workflow. Specifically, the volume of patients needing IVT frequently contributes to long patient wait times, and this is compounded by the need for serial intravitreal injections, further exacerbating the burden on patients, their family members, and care providers. Finally, the lack of consensus on ocular anesthesia choice among retina physicians suggests that there is currently no ideal ocular anesthetic for IVT. Developing a method of anesthesia that provides consistent pain control while reducing patient wait times is expected to result in improved patient care. This phase 1 study of 44 eyes receiving IVT demonstrates that cooling anesthesia is safe, well-tolerated, and resulted in time savings compared to lidocaine-based anesthesia. Ultra-rapid cooling for ocular anesthesia may reduce chair time for the patient, thus potentially decreasing patient visit times and improving clinic flow. In addition, patients receiving cooling anesthesia at −10°C for 20 seconds had comparable anesthetic control to lidocaine-based anesthesia and demonstrated a reduction in post-IVT discomfort.
Despite the frequency of IVT, there is a lack of evidence-based data to guide the selection of an optimal anesthetic.19 Blaha and colleagues conducted a randomized trial of anesthetic methods for IVT, specifically comparing 0.5% proparacaine, 0.5% tetracaine, a 4% lidocaine pledget, and a subconjunctival injection of 2% lidocaine.20 Mean injection pain scores were 2.8 for 0.5% proparacaine, 3.1 for 0.5% tetracaine, 3.0 for the 4% lidocaine pledget, and 2.3 for 2% subconjunctival lidocaine.20 There was no statistically significant difference in pain scores between any of the anesthetic approaches. Cohen and colleagues compared pain scores following extended exposure to subconjunctival lidocaine (SCL) and 0.5% tetracaine gel.21 In that study, subjects received proparacaine plus either 4 applications of 0.5% tetracaine gel over 12 minutes or 6 minutes of tetracaine gel followed by 6 minutes of SCL.21 For eyes receiving SCL, mean pain was 0.75, with a mean pain of 1.93 for eyes receiving 4 applications of 0.5% tetracaine gel.21 These findings suggest that longer exposure times help lower IVT pain for subjects receiving SCL. It is important to note that injection pain scores achieved in the Cohen, et al. study with 12 minutes of exposure to topical lidocaine gel are similar to pain scores obtained in groups 4 and 5 of this study, though cooling anesthesia achieved those scores with 10 to 20 seconds of anesthesia time. In this study, eyes receiving SOC were given approximately 5 minutes of exposure time to lidocaine in an attempt to maximize anesthetic efficacy. Shorter times have been demonstrated to result in more painful injections for patients, which would have skewed our results.
The results of this first-in-human trial support using ultra-rapid cooling as a novel alternative to lidocaine-based ocular anesthesia. The physiology of cooling-induced nerve conduction blockade has been studied for decades. When myelinated and unmyelinated fibers reach a temperature of approximately 0°C, nerve conduction ceases.14 The time it takes for nerve conduction to return to normal depends on the degree of cooling, with anesthesia lasting up to several days in cases of extended freezing that causes transient nerve damage.14 In this study, all subjects were exposed to temperatures between −5°C and −10°C for short periods of time. The short duration of cooling, combined with the intrinsic heat generated by the eye likely resulted in tissue temperatures remaining above 0°C even when the device temperature was set at −5°C and −7°C. This may explain the incomplete anesthetic effect noted in subjects in Groups 1–3 and helps explain the dose response curve. Another factor of the short contact time is the relatively short window of effect before the tissue temperatures likely returned to normal, allowing for pain conduction. Our team used ANSYS-Fluid software (Canonsburg, PA, USA) to model conjunctival and scleral temperature following exposure to the cooling device at −10°C, and ocular tissue temperature changed in a matter of seconds. In this study, subjects had a mandatory minimum 15 second waiting period after cooling application to allow for additional betadine treatment before IVT. It is possible that some of the cooling effect may have worn off during this waiting period. However, even with this warming period, subjects in the −10°C temperature (Groups 4–5) achieved anesthesia levels comparable to SOC applied for a minimum of 3 minutes, suggesting that this temperature was cold enough to result in clinically meaningful nerve conduction blockade.
The safety of ocular cryotherapy has been extensively studied in the literature, due in large part to the advent of liquid-nitrogen-based cryotherapy to treat ocular tumors and retinal tears in the late 1960s. Curtin and colleagues22 examined the effect of −40°C applied to rabbit sclera via histopathology. The temperature was applied until retinal whitening was seen. Following removal of the eyes, histopathologic evaluation showed minor cell loss at days 2 and 4 post treatment. These changes were no longer apparent at days 7, 14, and 21 post treatment. Prior to initiation of this trial, a pre-clinical ocular safety study was performed in rabbits. A handheld thermoelectric cooling device capable of reaching temperatures much lower than the clinical trial prototype was developed to rapidly anesthetize a 4 mm × 4 mm area on the surface of the eye. Twenty rabbits (40 eyes) were divided into 2 groups, with the first group receiving a 10 second treatment, and the second group receiving a 30 second treatment. All animals received 4 treatments per eye, with one treatment in each quadrant. Ten temperatures were tested, ranging from +20°C to −40°C. All eyes were examined by a board-certified veterinary pathologist and there was no histopathologic sign of ocular toxicity in rabbits treated at temperatures as cold as −30°C for 30 seconds. At −35°C and −40°C, mild limbal inflammation was observed in a small subset of eyes.16
In the human feasibility study, the coldest temperature utilized was −10°C, which is warmer than the −20°C threshold that has been shown to result in reversible signs of histopathologic damage.23 Our study participants were examined immediately following cooling treatment and again 24 hours post-treatment, and there was no clinical evidence of marked toxicity noted in any subject. Similarly, no subjects reported pain associated with the application of the cooling device. This is likely secondary to the warmer temperature of the cooling device (−5°C to −10°C) compared to the temperatures of standard, liquid nitrogen-based ocular cryotherapy (−50°C to −80°C). In addition, the duration of exposure for cooling anesthesia never exceeded 20 seconds, with approximately half the patients receiving 10 second treatment. The shorter duration of treatment may have also contributed to the lack of any clinical discomfort during or following the application of cooling. Although the focal cooling is applied immediately posterior to the limbus overlying the area of ciliary body, the internal temperature experienced by the ciliary processes is much lower than what would be required to destroy the ciliary processes with single or multiple applications. In addition, the area treated by focal cooling is less than 1 clock hour, which is much smaller than 3 to 6 clock hours that would be required to lower intraocular pressure.
In conclusion, this prospective, randomized, phase 1 clinical trial of a cooling anesthesia device demonstrated clinical safety and tolerability of ultra-rapid cooling as a novel method of ocular anesthesia. In addition, subjects treated with colder temperatures and longer time periods achieved anesthesia levels comparable to SOC. Given the relatively small sample size of this pilot study and lack of masking inherent to phase 1 trial design, additional studies, including time-and-motion studies are needed to validate the efficacy, safety and potential patient time-savings of cooling anesthesia for clinical use in the administration of IVT.
Supplementary Material
MPEG4 movie demonstrating cooling anesthesia applied to the ocular surface prior to delivering intravitreal injection.
Acknowledgments:
The authors wish to thank Gunho Kim for engineering support.
Financial Support: Coulter Translational Research Partnership Program, University of Michigan; MTRAC for Life Sciences Innovation Hub, University of Michigan; Fostering Innovation Grants, University of Michigan Health System, National Institute of Health/ National Eye Institute SBIR Grant 1R44EY028495. The funding organizations had no role in the design or conduct of this research.
Abbreviations:
- VAS
Visual analog scale
- VEGF
Vascular Endothelial Growth Factor
- SOC
Standard of care
- IVT
Intravitreal treatment
- DME
Diabetic macular edema
- SCH
Subconjunctival hemorrhage
- SCL
Subconjunctival lidocaine
- AMD
Age-related macular degeneration
Footnotes
Conflict of Interest: C.G.B, S.J.S, and K.P.P. have royalty and equity interests in iRenix Medical. S.J.S. is an employee of iRenix Medical. C.G.B and D.N.Z have royalty interest in ONL Therapeutics. D.C.M is a consultant for ONL Therapeutics.
This article contains a video as additional online-only material. The following should appear online-only: Clip 1.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
MPEG4 movie demonstrating cooling anesthesia applied to the ocular surface prior to delivering intravitreal injection.