Ophthalmic Technology Assessment Management of Pain after Photorefractive Keratectomy A Report by the American Academy of Ophthalmology Walter Allan Steigleman, MD,1 Jennifer Rose-Nussbaumer, MD,2 Zaina Al-Mohtaseb, MD,3 Marcony R. Santhiago, MD,4 Charlies C. Lin, MD,5 Seth M. Pantanelli, MD,6 Stephen J. Kim, MD,7 Julie M. Schallhorn, MD8 Objective: To evaluate current best practices for postoperative photorefractive keratectomy (PRK) pain control. Methods: Literature searches in the PubMed database were last conducted in October 2021 and were restricted to publications in English. This search identified 219 citations, of which 84 were reviewed in full text for their relevance to the scope of this assessment. Fifty-one articles met the criteria for inclusion; 16 studies were rated level I, 33 studies were rated level II, and 2 studies were rated level III. Results: Systemic opioid and nonsteroidal anti-inflammatory drugs (NSAIDs); topical NSAIDs; postoperative cold patches; bandage soft contact lenses (BCLs), notably senofilcon A contact lenses; and topical anesthetics were demonstrated to offer significantly better pain control than comparison treatments. Some other commonly reported pain mitigation interventions such as systemic gabapentinoids, chilled intraoperative balanced salt solution (BSS) irrigation, cycloplegia, and specific surface ablation technique strategies offered limited improvement in pain control over control treatments. Conclusions: Systemic NSAIDs and opioid medications, topical NSAIDs, cold patches, BCLs, and topical anesthetics have been shown to provide improved pain control over alternative strategies and allow PRK-associated pain to be more tolerable for patients. Ophthalmology 2023;130:87-98 ª 2022 by the American Academy of Ophthalmology The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an Ophthalmic Technology Assessment is to review the available research for clinical efficacy, effectiveness, and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The purpose of this assessment by the Ophthalmic Technology Assessment Committee Refractive Management/Intervention Panel was to evaluate the scientific literature pertaining to the management of pain after photorefractive keratectomy (PRK). laser-assisted subepithelial keratomileusis (LASEK), and epi-LASIK. Because most of the studies included in this assessment are based on PRK, this terminology will be used to refer to surface ablation techniques unless a specific type of procedure is being evaluated. Post-PRK pain typically increases quickly on the day of the procedure and peaks 1 to 3 days postoperatively.1,2 Such pain is hypothesized to be related to corneal nerve fiber exposure and injury from corneal epithelial debridement and stromal tissue laser ablation, and it usually subsides once the epithelium heals.1,3 Numerous methods for postoperative PRK pain control have been suggested, including systemic agents, topical medications, technique modifications, bandage soft contact lenses (BCLs), and cryoanalgesia, and they are evaluated and compared next. Background Questions for Assessment Despite excellent surgical outcomes similar to those for LASIK, surface excimer ablation is associated with more postoperative pain and discomfort. Multiple procedures can be categorized as surface ablation and are collectively known as “advanced surface ablation.” These include PRK, The focus of this assessment is to address the following questions: (1) What are current best options for postoperative PRK pain control? and (2) Which methods have been demonstrated to have a clinically important impact on pain control? ª 2022 by the American Academy of Ophthalmology Published by Elsevier Inc. https://doi.org/10.1016/j.ophtha.2022.07.028 ISSN 0161-6420/22 87 Ophthalmology Volume 130, Number 1, January 2023 Description of Evidence Literature searches in PubMed database, restricted to publications in English, were conducted in February 2019, January 2020, August 2020, and October 2021. Search terms for this review included the following: photorefractive keratectomy[tiab] OR PRK [tiab] OR photorefractive keratectomy[mh] OR advanced surface ablation[tiab]. (pain, postoperative/drug therapy[mh] OR bandages, hydrocolloid[mh])) OR bandage contact lens[tiab]) OR anti-inflammatory[tiab]) OR analgesics[tiab]) OR acetaminophen [tiab]) OR codeine[tiab]) OR opioids[tiab]) OR placebo[tiab]) OR therapeutic soft contact lens[tiab]) OR (homatropine OR diclofenac OR cyclopegic OR nsaid OR RGTA OR comfilcon OR senofilcon)) OR cold patch [tiab]) OR hydrogel bandage[tiab]) OR (fentanyl OR TDF OR pregabalin OR gabapentin OR bromfenac OR lotrafilcon OR omafilcon OR nepafenac). This search identified 219 citations, of which 84 were reviewed in full text. Fifty-one articles met the following inclusion criteria: (1) The primary objective of the study was to evaluate pain control or healing after PRK, (2) the study reported pain outcomes after corneal refractive surgery, (3) the study represented original research, and (4) patients were followed to re-epithelialization or BCL removal. The panel methodologist (J.R.R-N.) assessed the quality of these studies and assigned a level of evidence rating according to the scale developed by the Oxford Centre for EvidenceBased Medicine.4 A level I rating was assigned to well-designed and well-conducted randomized controlled trials. A level II rating was assigned to well-designed, retrospective, case-controlled, and cohort studies and lower-quality randomized studies. A level III rating was assigned to comparative case series, case reports, and lowerquality case-controlled or cohort studies. Sixteen articles were rated level I, 33 articles were rated level II, and 2 articles were rated level III. However, the level III articles were not included in this assessment. Pain is a complex biopsychosocial process that is inherently subjective. Thus, it is challenging to establish metrics to evaluate it objectively. Most of the included studies used 1 or more survey tools that rate pain on a continuum. One widely used validated tool is the visual analogue scale (VAS) that patients use to report pain from 0 mm (no pain at all) to 100 mm (worst pain imaginable). Some VAS reports are from 0 to 10 cm, similar to the 10point numerical pain rating scale. Additional pain rating tools, including the Brief Pain Inventory, McGill Pain Questionnaire Rating Index, and ad hoc questionnaires, were used in a minority of the studies, and results were not compared systematically.1-3 The VAS or similar decile results were used for this assessment because that scale was used for the majority of evaluated studies. For VAS results reported in millimeters, a simple conversion to centimeters was made for tabular comparisons. For results reported in alternative pain-rating scales with ranges other than 10, a simple conversion ratio was used to convert results to a 10-point scale for comparisons. As discussed next, reported pain levels peaked the 88 day of or the day after surgery. Some studies reported pain results for other time points as well; however, these data were limited and variable. All evaluated studies reported pain survey data for postoperative day (POD) 1. Therefore, pain levels reported for POD1 or otherwise closest to 24 hours after surgery were used for comparisons in this assessment. Study results listed as “similar” were not reported as statistically significantly different in the respective articles. For clinical context, Myles et al5 reported that for postoperative pain a change of 1 cm on the VAS was deemed a minimally clinically important difference, and a pain score of 3.3 cm or less indicated acceptable pain control. Interventions meeting these thresholds may be more notable when comparing options to optimize pain control for patients post-PRK. Published Results Typical Course of Post-PRK Pain Several studies have evaluated patient-reported pain postPRK on a prospective basis. These studies have found that post-PRK pain peaks the day of or the day after surgery and then decreases until re-epithelialization is complete, which for most patients occurs by 96 hours after surgery.1-3 Almost all patients report post-PRK pain, and a majority report the pain levels as severe ( 7/10) for at least a portion of the recovery period.1 The reported peak VAS scores ranged between 4.92 and 7.3 Post-PRK pain was correlated with reduced visual functioning and negative impacts on patients’ quality of life.1 Published evidence suggests that parameters such as sex, age, preprocedural anxiety, and depth of ablation appear to have limited impact on reported postoperative pain.1-3,6 Pain Control Interventions Systemic Agents A common approach to ameliorate postoperative pain is to use systemic pain medications to reduce activity in pain receptors and central pain processing. A total of 6 studies evaluated systemic agents for post-PRK pain control; 2 evaluated systemic opioids, 1 evaluated systemic nonsteroidal anti-inflammatory drugs (NSAIDs), and 3 evaluated systemic gabapentinoids (Table 1). Two studies evaluating opioid medication demonstrated efficacy in pain control. Opioids modulate nociceptive responses via primarily opioid mu receptors.7 Peripheral painsensing nerve fibers possess opioid receptors that appear to reduce excitability and the release of proinflammatory mediators similar to opioid-mediated actions in central nerve processes.8 Treatment with opioid receptor agonists may modulate both central and peripheral pain perception. A level I contralateral eye study by Pereira et al9 compared an oral opioid combination of codeine and acetaminophen with placebo in 80 eyes of 40 patients. The contralateral approach for a systemic agent was Steigleman et al Ophthalmic Technology Assessment Table 1. Systemic Pain Medications Year Level of Evidence Study Design 2013 I RCT (124) Kuhnle 2011 I RCT 83 Lee11 2014 II Cohort Meek12 2014 I RCT 135 Pakravan13 2012 I RCT 150 10 Palochak 2021 I RCT 197 Pereira9 2017 I RCT* (80) Author 15 Eslampoor 14 No. of Patients (Eyes) (398) Comparison Oral diclofenac Acetaminophen/ibuprofen Gabapentin Placebo Transdermal fentanyl Oral tramadol Pregabalin Placebo Pregabalin or gabapentin Placebo Codeine/acetaminophen Oxycodone/acetaminophen Codeine/acetaminophen Placebo POD1 Pain Score 4.32 6.52 3.85 4.09 2.72 1.99 2.05 2.38 2.83 4.61 2.132 2.195 2.709 2.503 4 2.4; 4.3 2.7 4.7 3 1.61 1.67 2.09 1.71 4 (95% CI, 3e6) 7 (95% CI, 6e9) Findings Diclofenac better P < 0.001 Similar P ¼ 0.64 Fentanyl better P < 0.001 Similar P ¼ 0.18 Similar P ¼ 0.265 Similar P ¼ 0.051 Codeine combo better P < 0.001 CI ¼ confidence interval; POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Contralateral study. achieved by spacing fellow eye surgery by approximately 2 weeks. The active medication group reported significantly less pain at all time points measured, with median pain scores of 4/10 in the treatment cohort and 7/10 in the placebo at 24 hours postoperatively, with a mean difference of e2.55 (95% confidence interval, e3.29 to e1.81, P < 0.001). The only side effect reported in the treatment group was more drowsiness. Another level I study comparing combination oral codeine/acetaminophen with oxycodone/acetaminophen found similar pain on POD1, but the codeine group (2.84 2.03) had statistically significantly lower reported pain on POD2 than the oxycodone group (3.58 2.29, P ¼ 0.017). Additionally, total pain tablets consumed were higher on POD2 as were the number of tetracaine drops used on POD1, 2, and 3 in the oxycodone cohort, suggesting that pain control was better in the codeine-treated group.10 A level II evaluation by Lee et al11 compared a single application of transdermal fentanyl (TDF) patches (12.5 mg/hour) to oral combination tramadol/acetaminophen for post-PRK pain in 398 eyes of 199 patients. Each medication was given 2 hours before surgery to achieve therapeutic dosing preoperatively. The oral medication was continued every 12 hours through the evening of POD3. The TDF cohort reported significantly less pain on the day of surgery and on POD1, with the largest difference being a mean VAS of 28.3 mm in the TDF cohort and 46.1 mm in the oral combination group (P < 0.001) on the morning after surgery.11 No other time points had significant differences. Nausea and vomiting occurred in 13.6% of TDF patients and in no patients in the tramadol group. No differences in visual outcomes were noted between the groups throughout 3 months of follow-up. Several studies evaluating gabapentin and pregabalin for postoperative pain control did not demonstrate robust efficacy. In a level I study of 135 patients comparing 75 mg oral pregabalin with placebo, no significant difference in reported pain in either cohort was found. However, patients receiving pregabalin had reduced rescue pain medication use, which included pro re nata oral combination oxycodone/acetaminophen, oral over-the-counter analgesics, and topical tetracaine drops.12 More adverse central nervous system effects, including somnolence, dizziness, or lightheadedness, were reported in the treatment group (24% of patients receiving pregabalin vs. 11% of controls [no P value was reported]). In a level I study, Pakravan et al13 compared 3 cohorts of 50 patients each receiving pregabalin, gabapentin, or placebo. Compared with the treatment cohorts, the placebo group had similar mean pain levels at all time points and used similar rescue pain medication quantities, but a higher proportion of patients reported severe pain greater than 7/10 on POD1 (P < 0.043). The pregabalin and gabapentin cohorts had similar pain scores, rescue medication use, and severe pain. A level I study by Kuhnle et al14 evaluated 83 patients treated with gabapentin or placebo and found no benefit for the treatment group. Eslampoor et al15 conducted a level I study comparing the oral NSAID diclofenac with a combination of acetaminophen/ibuprofen in 62 patients. Each medication was dosed preoperatively only; the extended-release diclofenac was dosed the night before and on the morning of surgery, and the combination medication was dosed only on the morning of surgery. The diclofenac group had significantly decreased pain, conjunctival injection, eyelid swelling, photophobia, and functional activity score when compared with the acetaminophen/ibuprofen combination (Table 1). Topical NSAIDs A total of 9 studies, which support the efficacy of topical NSAIDs for pain control, were evaluated and are summarized in Table 2. Three studies evaluated a single application of topical NSAID (diclofenac or ketorolac) preoperatively to control postoperative pain. All studies demonstrated a significant 89 Ophthalmology Volume 130, Number 1, January 2023 degree of pain relief with the topical NSAID. In one level II study, postoperative pain decreased from a mean VAS of 7 in the placebo group to 3 in the NSAID group (P < 0.0001).16 In a different level II study, pain was reduced from a mean VAS of 2.09 in the placebo group to 0.97 in the NSAID group.17 Six studies evaluated numerous different postoperative topical NSAIDs. A level I study by Vetrugno et al18 of postoperative administration of flurbiprofen, ketorolac, diclofenac, and indomethacin compared with placebo demonstrated similar efficacy of all NSAIDs. It found that ketorolac, diclofenac, and indomethacin had delayed reepithelialization when compared with placebo and flurbiprofen.18 A level II study by Sher et al19 compared topical bromfenac with topical ketorolac in 212 eyes. No differences in pain control between groups and no adverse events, including re-epithelialization delays, were noted. A level II study by Trattler and McDonald20 was planned to compare topical ketorolac with topical nepafenac in a contralateral eye study in 60 eyes of 30 patients. This study noted no difference in pain control on POD1 but was halted after enrolling 14 patients because of a concern for slower healing, more corneal haze, and increased pain in the nepafenac cohort. Of note, this study was funded by a grant from the manufacturer of topical ketorolac.20 One level II study compared the topical NSAID 0.4% ketorolac twice daily with the oral NSAID naproxen, dosed 220 mg twice daily, and found that POD1 pain was lower in the topical group (ketorolac 3.21 2.09 vs. oral 5.17 2.25, P < 0.0001) despite similar levels of pain control on the day of surgery.21 Eslampoor et al22 evaluated the addition of topical diclofenac to oral diclofenac in a level II study and found it offered no difference in reported pain, but it did result in less postoperative edema and conjunctival injection than the placebo drop. In a level II study of 70 eyes of 35 patients, Shetty et al23 compared a BCL preoperatively soaked in nonpreserved ketorolac with a standard lens applied at the completion of the PRK procedure. This approach demonstrated a significant reduction in postoperative pain in the treated contact lens group without any adverse events reported (ketorolac-soaked lens 2.76 0.85 vs. standard lens 7.95 2.12, P < 0.001). Cryoanalgesia Another modality evaluated for post-PRK pain control is the use of chilled agents applied either to the ocular surface or periocular tissues (Table 3). The use of postoperative cold patches seems to be effective in reducing postoperative pain. A level II study by Zeng et al24 of cold patches over the eyelids applied every 30 minutes for 24 hours while patients were awake found that the patches resulted in significantly less pain (cold patch 2.16 1.31 vs. 3.25 1.03 balanced salt solution [BSS] wash, P ¼ 0.001), as well as less swelling and conjunctival hyperemia. The use of intraoperative chilled BSS for irrigation was not found to be effective in reducing pain in both level I and level II studies.25,26 90 Cycloplegia The role of cycloplegic agents in reducing the pain associated with ciliary spasm after PRK was evaluated in 2 studies (Table 4). A level II study of homatropine dosed twice daily found that the homatropine group had significantly lower pain scores (homatropine 2.5 1.9 vs. 5.3 2.5 placebo, P ¼ 0.004 at 24 hours) and no delay in re-epithelialization.27 A level II study by Aghdam et al28 compared homatropine with treatment with topical diclofenac in 64 eyes of 32 patients and found the NSAID cohort had significantly less pain at all time points. Bandage Soft Contact Lenses Bandage soft contact lenses currently are the standard of care for patients undergoing surface ablation procedures, and they have been found to aid epithelial healing and decrease pain and corneal haze formation.29,30 Currently, 3 soft contact lenses are Food and Drug Administration approved for therapeutic use, including balafilcon A (Purevision, Bausch & Lomb), lotrafilcon A (Air Optix Night and Day Aqua, Alcon), and senofilcon A (Acuvue Oasys, Johnson & Johnson). The remaining lenses included here are considered off-label for use as BCLs in the United States. Fourteen studies comparing the post-PRK use of various soft BCL materials until re-epithelialization to control pain and modulate healing were included in this assessment. There was much heterogeneity in the reported postoperative pain-control protocols; topical NSAIDs, oral NSAIDs, and oral acetaminophen with or without narcotic combinations were prescribed in addition to placing a BCL. All but 1 of the studies31 were randomized, contralateral eye comparison trials that should help reduce the influence of factors other than the BCL intervention on reported pain. Overall, these studies found less pain with senofilcon A contact lenses. A summary of studies on contact lenses is listed in Table 5. Epithelial Removal Techniques A variety of procedures known as advanced surface ablation involve different epithelial removal methods with or without repositioning of the epithelium. The most common procedure, PRK, typically includes using either a rotary brush or mechanical scraping methods for epithelial debridement. Laser-assisted subepithelial keratomileusis usually involves using ethanol 20% to soften epithelial adhesion to the underlying Bowman’s membrane. This is followed by careful separation of an epithelial flap with the intention of replacing it after stromal ablation with the excimer laser. Epi-LASIK entails using an epithelial microkeratome to separate the epithelium from underlying Bowman’s membrane, with the intention of repositing the flap after excimer ablation. A total of 8 studies compared pain after different epithelial removal techniques (Table 6). There was heterogeneity in postoperative pain-control regimens between studies, in which various topical, oral, and therapeutic soft contact lens materials were used. Overall, there was no consistent trend in pain control in studies comparing LASEK with PRK. One level II study by Steigleman et al Ophthalmic Technology Assessment Table 2. Topical NSAIDs Level of Year Evidence Study Design 2014 II RCT 68 2014 II RCT* (188) Mohammadpour17 2011 II RCT* (140) Razmju16 2012 II RCT* (166) Ripa21 2020 II RCT 157 19 Sher 2009 II RCT* (212) Shetty66 2019 II Case Series (70) Trattler20 2007 II RCT* (60) Vetrugno18 2000 I RCT 25 Author 22 Eslampoor 51 Hong No. of Patients (Eyes) 25 25 25 Comparison POD1 Pain Score Findings Oral NSAID alone Addition of topical diclofenac Preoperative diclofenac or ketorolac No preoperative topical NSAID Preoperative topical diclofenac Placebo Preoperative diclofenac or ketorolac Placebo Topical ketorolac Oral naproxen Postoperative bromfenac Postoperative ketorolac Ketorolac-soaked BCL Standard BCL Ketorolac for epi-LASIK Nepafenac for epi-LASIK Topical flurbiprofen Placebo Topical ketorolac Placebo Topical diclofenac Placebo Topical indomethacin Placebo 3.97 2.67 4.32 2.72 2.6, 3.0y 4.4y 0.97 1.97 2.09 3.36 3.0 7.0 3.21 2.09 5.17 2.25 1.8y 1.8y 2.76 0.85 7.95 2.12 0.6 1.4 3.72z 6.16z 4.52z 6.16z 4.58z 6.16z 5.32z 6.16z Similar P ¼ 0.850 NSAID better P < 0.001 Diclofenac better P ¼ 0.018 NSAID better P < 0.0001; P ¼ 0.0002 Ketorolac better P < 0.0001 Similar "No differences" Ketorolac-soaked better P < 0.0001 Similar P > 0.05 Flurbiprofen better P < 0.0001 Ketorolac better P < 0.0001 Diclofenac better P < 0.0001 Indomethacin better P < 0.0001 BCL ¼ bandage soft contact lens; NSAID ¼ nonsteroidal anti-inflammatory drug; POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Contralateral study. y Value interpolated from graph. z Pain rating adjusted to 10-point scale. Ghanem et al32 found similar pain between LASEK and PRK, whereas a different level II study found that PRK patients had significantly less postoperative pain than LASEK patients.33 A level II study by Wang et al34 found that LASEK eyes had significantly less pain on POD1 than PRK eyes, with no difference at POD2 and POD3. A level II contralateral eye study by Eliacik et al35 found that the LASEK group had less POD1 pain (P ¼ 0.001) but that the PRK group had faster re-epithelialization (3.07 0.64 vs. 3.55 0.54 days, P ¼ 0.03). As with LASEK, there was not a consistent trend in outcomes favoring epi-LASIK or PRK for postoperative pain. A level II study by O’Doherty et al36 comparing epi-LASIK, LASEK, and PRK found no difference in reported pain at 24 hours after surgery. A level II contralateral eye study by Magone et al37 found that patients receiving epi-LASIK had 0.33 units less pain on a 6-point pain scale (P ¼ 0.0003), a difference that the authors noted was likely clinically insignificant. Sia et al38 reported a level II study comparing epiLASIK with PRK and found similar postoperative pain levels. Torres et al39 found no difference between manual debridement PRK and epi-LASIK in a level I contralateral eye study. A level II study by Skevas et al40 found no difference in pain between epi-LASIK and PRK (Table 6). Table 3. Cryoanalgesia Techniques Author 25 Year Level of Evidence Study Design No. of Eyes Neuffer 2013 II RCT* 80 Zarei-Ghanavati26 2017 I RCT* 100 Zeng24 2015 II RCT 80 Comparison Chilled BSS intraoperatively Room temperature BSS intraoperatively Chilled BSS and BCL Room temperature BSS and BCL Cold patch postoperatively Chilled BSS intraoperatively POD1 Pain Score y 3.1 3.3y 1.72.24 1.72 2.13 2.16 0.81 3.25 1.03 Findings Similar P > 0.05 Similar P ¼ 0.87 Cold patch better P ¼ 0.001 BCL ¼ bandage soft contact lens; BSS ¼ balanced salt solution; POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Contralateral study. y Value interpolated from graph. 91 Ophthalmology Volume 130, Number 1, January 2023 Table 4. Cycloplegic Medications Study Design No. of Eyes Aghdam28 Author Year 2015 II Level of Evidence RCT* 64 Joshaqhani27 2013 II RCT* 30 Comparison Topical diclofenac Homatropine Homatropine Placebo POD1 Pain Score Findings Diclofenac better P < 0.001 Homatropine better P ¼ 0.004 1.7 5.8 2.5 5.3 1.4 2.1 1.9 2.5 POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Contralateral study. Topical Anesthetics Local anesthetics exert their effect by blockading voltagegated sodium channels, thereby limiting nerve conduction in pain fibers.41 Tetracaine is a topical anesthetic commonly used to complete a host of ophthalmic procedures. A level II study of 44 patients by Verma et al42 compared nonpreserved tetracaine 1% with placebo for post-PRK pain control in 44 patients. The drops were applied halfhourly while the patient was awake for the first 24 hours postoperatively. Tetracaine was more effective at pain control than placebo, with a maximum pain level of 2.5 versus 6.5 for the placebo cohort (P < 0.0001). All patients had full re-epithelialization by 72 hours. Table 5. Bandage Soft Contact Lens Year Level of Evidence Study Design No. of Eyes AlDahash57 Author 2021 II RCT* 112 Bagherian67 2020 I RCT* 90 Duru68 2020 I RCT* 86 Duru69 2020 I RCT* 74 Edwards31 2008 II Cohort 206 Eliacik70 2015 II RCT* 42 Grentzelos71 2009 I RCT* 88 Mohammadpour8 2017 II RCT 260 72 Mohammadpour 2015 II RCT* 120 Mohammadpour73 2018 II RCT* 120 Mukherjee74 2015 I RCT* 48 Razmjoo75 2012 II RCT* 88 30 Taneri 2018 I RCT* 30 Taylor55 2014 II RCT* 36 36 36 Yuksel76 2019 II RCT* 68 Comparison Exchanged at POD1 Not exchanged Balafilcon A (PureVision) Balafilcon A (PureVision2) Senofilcon A Lotrafilcon B Samfilcon A Balafilcon A Lotrafilcon A Omalfilcon A Comfilcon A Lotrafilcon B Lotrafilcon A Lotrafilcon B 4-day BCL removal 7-day BCL removal Lotrafilcon B Balafilcon A Lotrafilcon B Comfilcon A Senofilcon A Comfilcon A Senofilcon A Lotrafilcon A Balafilcon A No contact lens Senofilcon A Balafilcon A Senofilcon A Lotrafilcon A Lotrafilcon A Balafilcon A Samfilcon A Lotrafilcon B BCL ¼ bandage soft contact lens; POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Contralateral study. y Mean calculated from raw data in manuscript. z Pain rating adjusted to 10-point scale. x Value interpolated from graph. 92 POD1 Pain Score 1.87 1.4 2.29 1.3 3.5y,z 3.8y,z 3.42 2.47 5.47 2.28 3.11 2.90 6.22 2.81 1.01z 3.95z 4.0 1.75z 5.5 2.5z 2.5z,x 2.5z,x 5.42 3.20 5.86 3.36 4.43 5.45 3.75 3.32 4.47 3.60 1.5 2.5 4.6 2.7 2.45 2.93z 6.25 2.43z 2.6x 4.8x 1.8 5.8 2.5 4.4 2.1 4.7 4.88 1.29 7.12 1.57 Findings Exchanged better P ¼ 0.009 Similar P > 0.05 Senofilcon A better P < 0.001 Samfilcon A better P < 0.001 Lotrafilcon A better P ¼ 0.000 Comfilcon A better P ¼ 0.011 Similar P > 0.10 Similar P ¼ 0.20 Lotrafilcon B better P ¼ 0.032 Similar P ¼ 0.253 Senofilcon A better P < 0.005 Senofilcon A better P ¼ 0.0001 Balafilcon A better P ¼ 0.003 Senofilcon A better P < 0.001 Senofilcon A better P ¼ 0.012 Lotrafilcon A better P < 0.001 Samfilcon A better P < 0.001 Steigleman et al Ophthalmic Technology Assessment Table 6. Surgical Epithelial Removal Techniques Year Level of Evidence Study Design Eyes Eliacik35 Author 2015 II RCT* 56 Ghanem32 2008 II RCT* 102 Ghirlando33 2007 II RCT* 100 Magone37 2012 II RCT* 120 O’Doherty 2007 II Clinical trial* 95 Skevas40 2013 II Clinical trial 209 Torres39 2007 I RCT* 40 Wang34 2014 II RCT* 60 36 Comparison LASEK PRK Butterfly LASEK PRK PRK LASEK Epi-LASIK PRK Epi-LASIK, LASEK PRK Epi-LASIK PRK Epi-LASIK PRK LASEK PRK Pain Level POD1 5.7 0.88y 8.84 1.0y 1.46 2.16y 2.28 2.46y 5.43 2.18y 6.55 1.5y 3.63 0.9y 4.12 0.87y 3.4, 3.4y,z 3.8y,z 0.6 0.8 3.58 2.83 3.27 2.33 3.2 1.883 4.43 1.612 Findings LASEK better P ¼ 0.001 Similar P ¼ 0.07 PRK better P ¼ 0.02 Epi-LASIK better P ¼ 0.0003 Similar P > 0.05 Similar P ¼ 0.357 Similar P ¼ 0.95 LASEK better P ¼ 0.008 LASEK ¼ laser-assisted subepithelial keratomileusis; POD ¼ postoperative day; PRK ¼ photorefractive keratectomy; RCT ¼ randomized controlled trial. *Contralateral study. y Pain rating adjusted to 10-point scale. z Value interpolated from graph. Nonpreserved tetracaine 1% was compared with bupivacaine 0.75% in a level II trial.43 Patients were instructed to use the anesthetic drops half-hourly while awake for the first 24 hours postoperatively. The tetracaine group had significantly lower maximum pain of 3.5/10 than the bupivacaine group of 5.5/10 and lower overall pain when comparing the area under the curve for the first 24 hours (P ¼ 0.05). No epithelial toxicity or delayed healing was noted in either cohort, and epithelial healing rates were identical. A level I contralateral eye study compared diluted proparacaine (0.05%) with placebo for post-PRK pain control.44 The proparacaine group reported an average reduction in pain after instilling a drop by e1.75 þ 0.69 versus e0.85 þ 0.98 for the placebo group (P < 0.002). The duration of pain relief was significantly longer in the proparacaine group, with most respondents reporting “10e30 minutes” or “30e60 minutes,” whereas most of the placebo group reported “0 minutes” (P < 0.001). Notably, oral narcotic use was significantly lower in the proparacaine cohort of 1.6 pills/eye versus 2.6 pills/eye in the placebo cohort (P < 0.025). No difference in the rate of re-epithelialization was noted (Table 7). Discussion Multiple modalities for managing post-PRK pain with varying levels of efficacy were evaluated. Some, such as topical NSAIDs and BCLs, offered significant reduction in pain with limited side effects, suggesting that these approaches should be considered an integral part of the postoperative care of PRK patients. Other modalities, such as systemic medications, topical anesthetics, and cold patches, may offer a useful adjuvant to pain-control practices. Topical anesthetics deserve careful consideration for inclusion in the postoperative pain-control regimen. Both systemic opioids and systemic NSAID medications were more effective at pain control than placebo. However, opioid use is associated with unfavorable side effects and social impacts. Current evidence suggests that legitimate opioid prescriptions for injury or surgery have fueled the current opioid addiction crisis.45 The most common route for first exposure to opioids for persons who end up with opioid addiction is a legitimate prescription for an injury.46 More than 25% of select patient populations who were prescribed opioid medications for acute pain were reported to still be using them at 1 year.47 Alternative treatments are worth consideration. High-quality evidence suggests that a high-potency oral NSAID such as diclofenac may be a preferred medication for controlling postoperative PRK pain. Nonsteroidal medications interrupt cyclo-oxygenase pathways, which inhibit prostaglandin and other proinflammatory mediator production, thereby reducing pain and inflammation.48 Adding a topical NSAID to an oral one did not offer additional paincontrol benefits, suggesting that once pathways are saturated, additional NSAID dosing is not of clinical benefit.22 Topical NSAIDs, used both perioperatively and postoperatively, were more effective at pain control than placebo after PRK. There is no evidence to support the efficacy of one NSAID over another. Except for the prematurely terminated study by Trattler and McDonald,20 all the other studies that reported significant reductions in pain using the NSAID intervention satisfied the threshold of the minimally clinically important difference in postoperative pain reduction. Topical NSAIDs are associated with epithelial toxicity and even corneal melts.48 Some earlier studies evaluating topical NSAIDs for post-PRK pain did report delays in re-epithelialization.18,49 One post-PRK patient was reported to have had a corneal perforation, necessitating urgent penetrating keratoplasty after having used topical ketorolac hourly for 5 days postoperatively.50 93 Ophthalmology Volume 130, Number 1, January 2023 Table 7. Topical Anesthetic Medications Author 44 Year Level of Evidence Study Design Contralateral No. of Patients (Eyes) 1997 I RCT No (25) 43 Verma 1997 II RCT No 38 Verma42 1995 II RCT No 44 Shahinian Comparison POD1 Pain Score Findings Proparacaine 0.05% Placebo Tetracaine 1% Bupivacaine 0.75% Tetracaine 1% Placebo e1.75 0.69* e0.85 0.98* 3.5 5.5 2.5 6.5 Proparacaine better P < 0.002 Tetracaine better P ¼ 0.05 Tetracaine better P < 0.0001 POD ¼ postoperative day; RCT ¼ randomized controlled trial. *Reduction in pain. Except for the study by Trattler and McDonald, no topical NSAID study evaluated in this assessment reported adverse events in treated eyes, and visual outcomes were similar to nontreated eyes through up to 7 months of follow-up.51 Topical anesthetics, including tetracaine and dilute proparacaine, were shown to be effective for post-PRK pain control. Additionally, dilute proparacaine-treated patients used fewer rescue narcotic-containing pain pills, offering more evidence to suggest an analgesic effect of the drops.44 Despite having a longer duration of action than tetracaine, bupivacaine was not effective for pain control.43 Some clinicians have reservations about prescribing topical anesthetics because of reports of ocular toxicity, and delayed epithelial healing with infiltrates after PRK has been reported.52 Despite these concerns, toxicity was not observed in any patients treated with topical anesthetics in the studies evaluated for this assessment. In the tetracaineto-placebo comparison, all patients had full reepithelialization by 72 hours and visual outcomes were similar in the 2 cohorts throughout the 6-month follow-up period.42 The lack of toxicity in these studies was notable, given the high frequency (up to half-hourly while awake) dosing of the topical anesthetics. However, it must be clearly stated that these patients had aseptic surgically induced corneal abrasions, were highly motivated to do well after opting for an elective refractive procedure, and had immediate access to an ophthalmologist under closely supervised conditions. Prolonged use of topical anesthetic after PRK has been reported to result in significant ocular morbidity.11 Furthermore, reports in the medical literature document ocular morbidity and reduced vision associated with unsupervised topical anesthetic use, notably in patients prone to ocular injuries.53 Long-standing awareness of the potential for topical anesthetic abuse to result in permanent vision loss and even loss of the eye has given ophthalmologists great respect for the utility and the potential dangers associated with these medications.54 Therefore, very close monitoring of patients using topical anesthetic drops is warranted. Bandage contact lenses were found to be very effective at reducing pain and promoting epithelial healing after PRK. Compared with other Food and Drug Administrationeapproved BCL materials, senofilcon A offered the greater pain control. Taylor et al55 used 94 high-magnification microscopy to evaluate BCL geometry and found the senofilcon A lens had a tapered edge with the thinnest profile of the lenses studied. This unique geometry was postulated to be the etiology for the improved pain control by the study authors. Not specifically addressed in these evaluated studies was the correlation of BCL basecurvature with patients’ keratometry and reported pain. Taylor et al56 reported improved pain control with a BCL when these parameters were matched. This effect may have confounded some of the BCL outcomes where not specifically addressed. In a level II contralateral eye study, AlDahash et al57 reported that exchanging the BCL on POD1 resulted in less postoperative pain (exchanged 1.87 1.4 vs. unchanged 2.29 1.3, P ¼ 0.009). The authors postulate that inflammatory mediators may be adherent to the BCL, and removing them by replacing the lens results in less inflammation and pain. A notable drawback to some of the BCL studies is their industry support, which may have biased the findings. Postoperative cold patches were shown to have a statistically significant and likely clinically relevant reduction in average reported pain over chilled BSS irrigation with similar surgical outcomes.24 Tissue cooling has been reported to offer pain relief after ocular surgeries, including cataract and retinal detachment repair.28,58 Ice cryotherapy decreases levels of mediators involved in ocular inflammation, including interleukin-6 and interleukin-1B, vascular endothelial growth factor, and prostaglandin E2, as reported in the orthopedic literature.59 Cold patches may offer a useful adjuvant to the other interventions described in this report. Cycloplegia with homatropine was demonstrated to be superior to placebo yet inferior to a topical NSAID (diclofenac) for post-PRK pain control. The use of cycloplegic agents to treat pain associated with corneal abrasions, perhaps by reducing ciliary spasm, is a widely accepted management tool, although with limited evidence.60 Cycloplegia appears to offer limited additive utility to reduce post-PRK pain, especially when compared with other viable options. Some interventions were not effective. Gabapentinoids were not found to be effective, although fewer reports of severe pain and less use of rescue pain medications were reported in some patients receiving them. The gabapentinoid mechanism of pain control is incompletely understood but Steigleman et al Ophthalmic Technology Assessment may be related to neurotransmission reduction via calcium channels, thrombospondin, and other molecular control.61 The lack of effect for PRK-treated eyes has been postulated to be related to the need for a more protracted loading dose of the medication for optimal effect.12 Likewise, intraoperative chilled BSS irrigation does not appear to confer benefits over room temperature irrigation, and using it did not appear to confer a reduced risk for postoperative complications. Some earlier studies correlated the potential thermal impact of PRK on corneal haze development, and some surgeons used chilled BSS not specifically for patient pain control but as a way to mitigate haze risk.62 Modern excimer laser ablation profiles may reduce potential thermal impacts of treatment and may reduce the baseline risk of haze in treated patients. Clinical outcomes other than pain control were reported in some of the studies and should be considered when making management decisions. Despite using mitomycin C in all eyes with higher ablation depths, more corneal haze was noted through 3 months in eyes without a BCL.30 Also, as expected, when Mohammadpour et al63 compared the use of a BCL removed on POD4 versus POD7, both cohorts had similar pain control through re-epithelialization. However, the longer duration group had quicker visual acuity recovery and significantly fewer long-term complications such as filamentary keratitis, corneal haze, and recurrent erosions through the 6-month follow-up period. Thus, use of a BCL provides additional benefits beyond pain control that are important for recovery after PRK. In addition, a secondary analysis of the cohort using a codeine/acetaminophen combination described previously demonstrated that the treatment group had statistically significant better reported sleep (58% vs. 25%, P < 0.001) and activity levels (risk ratio, 3.0; 95% confidence interval, 1.5e6.1) than the placebo group. The authors postulate that patients with impaired sleep after surgery may experience increased sensitivity to pain and possible increased frequency of dry eye and related difficulties with ocular surface healing.64 In another contralateral eye study that compared the use of an intracanalicular steroid insert with topical steroid treatment, patients had similar reported postoperative pain and overall outcomes in the 2 eyes, yet had a strong preference for the insert. Patients reported that convenience was the number one reason for the preference.65 Increased compliance would presumably be expected with an insert. Although several methods of epithelium removal were evaluated in this assessment, there was no evidence to support the superiority of one technique over another in terms of pain control. However, as discussed for other paincontrol management strategies, multiple clinical factors in addition to pain control need to be balanced when selecting one procedure over another. Conclusions Despite the challenges of objectively evaluating postoperative PRK pain, notable improvements in control have been demonstrated with certain interventions in the ophthalmology literature. Topical NSAIDs and therapeutic soft contact lenses provided significant benefit with little downside. Systemic opioids were effective but have potential for addiction. Nonsteroidal anti-inflammatory medications, postoperative cold patches, therapeutic soft contact lenses, and topical anesthetics were found to offer significant reductions in reported pain. Some BCL studies had industry support, which may have biased the results. Clinical outcomes were reported as similar for these treatments when compared with alternative treatments. Some commonly reported pain mitigation interventions, such as systemic gabapentinoids, intraoperative chilled BSS irrigation, cycloplegia, and specific technique strategies, appear to offer limited statistical or clinical differences in pain control over comparison treatments. Future Research Despite the myriad approaches described in this assessment, pain symptoms are still common in this surgical population. Further improvements to interventions demonstrated to reduce post-PRK pain are needed. Pain has been correlated with size and duration of the epithelial defect. Interventions aimed at promoting rapid reepithelialization could prove to be very helpful in reducing post-PRK pain. Some systemic agents shown to reduce postPRK pain have been associated with untoward side effects such as opioid habituation. Development of topical versions of such agents may allow local pain control while minimizing systemic side effects. New comparisons of technique strategies such as method of epithelial debridement, excimer laser type, and even realistic surgeon descriptions of expected postoperative pain could be important factors in how patients experience post-PRK pain. Topical NSAIDs have been shown to be helpful in reducing post-PRK pain. Although not specifically noted to be problematic in the evaluated studies, topical NSAID use has been associated with delayed epithelial healing, punctate keratopathy, and corneal melts.48 Newer formulations or even novel delivery mechanisms such as that reported with BCL-associated NSAID delivery may allow for stable therapeutic levels that remain below toxicity levels. Cherry et al29 reported that a combination of paincontrol strategies appeared to be more effective than interventions used separately. Future efforts to discern the optimal mix of currently available pain-control management strategies could help improve PRK patients’ postoperative experience. Therapies for novel pain-associated pathways yet to be elucidated could allow PRK to have a more comfortable healing phase. Developing interventions to continue to modulate pain while also addressing other common patient concerns such as photophobia, burning sensation, itching, headache, epiphora, and foreign body sensation could have a significant positive impact in patients’ experience during post-PRK healing. 95 Ophthalmology Volume 130, Number 1, January 2023 Footnotes and Disclosures Originally received: July 22, 2022. Accepted: July 26, 2022. Available online: October 4, 2022. Manuscript no. OPHTHA-D-22-01320 Prepared by the Ophthalmic Technology Assessment Committee Refractive Panel and approved by the American Academy of Ophthalmology’s Board of Trustees June 25, 2022. 1 Funded without commercial support by the American Academy of Ophthalmology. HUMAN SUBJECTS: No human subjects were included in this study. The Institutional Review Boards approved the study and waived the requirement for informed consent because of the retrospective nature of the study. All research adhered to the tenets of the Declaration of Helsinki. University of Florida College of Medicine, Gainesville, Florida. 2 Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, California. 3 Baylor College of Medicine, Houston, Texas. 4 University of Sao Paulo, Sao Paulo, Brazil. 5 Stanford Eye Institute, Palo Alto, California. 6 Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania. 7 Department of Ophthalmology, Vanderbilt University School of Medicine, Nashville, Tennessee. 8 Francis I. Proctor Foundation and Department of Ophthalmology, University of California, San Francisco, California. Disclosure(s): The author(s) have made the following disclosure(s): Z.A-M.: Consultant fees e Carl Zeiss Inc., Alcon Laboratories, Bausch þ Lomb. M.R.S.: Consultant and lecture fees e Alcon Laboratories; Consultant fees e Ziemer Ophthalmics AG. S.M.P.: Lecture fees e Alcon Laboratories; Consultant fees e Carl Zeiss Meditec, Bausch þ Lomb. No animal subjects were included in this study. Abbreviations and Acronyms: BCL ¼ bandage soft contact lens; BSS ¼ balanced salt solution; LASEK ¼ laser-assisted subepithelial keratomileusis; NSAID ¼ nonsteroidal anti-inflammatory drug; POD ¼ postoperative day; PRK ¼ photorefractive keratectomy; TDF ¼ transdermal fentanyl; VAS ¼ visual analogue scale. Keywords: photorefractive keratectomy, pain management, PKR. Correspondence: Andre Ambrus, MLIS, American Academy of Ophthalmology, Quality and Data Science, P.O. Box 7424, San Francisco, CA 94120-7424. E-mail: [email protected]. J.M.S.: Consultant fees e Carl Zeiss Meditec, Johnson & Johnson Vision. The other authors have no proprietary or commercial interest in any materials discussed in this article. References 1. Sobas EM, Videla S, Vazquez A, et al. Pain perception description after advanced surface ablation. Clin Ophthalmol. 2017;11:647e655. 2. Garcia R, Horovitz RN, Torricelli AA, et al. Improved evaluation of postoperative pain after photorefractive keratectomy. 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Surv Ophthalmol. 1992;36:259e284. 49. Arshinoff S, D’Addario D, Sadler C, et al. Use of topical nonsteroidal anti-inflammatory drugs in excimer laser photorefractive keratectomy. J Cataract Refract Surg. 1994;20(Suppl):216e222. 50. Mian SI, Gupta A, Pineda 2nd R. Corneal ulceration and perforation with ketorolac tromethamine (acular) use after PRK. Cornea. 2006;25:232e234. 51. Hong JP, Nam SM, Im CY, et al. Comparison of analgesic effect of preoperative topical diclofenac and ketorolac on postoperative pain after photorefractive keratectomy. J Cataract Refract Surg. 2014;40:1689e1696. 52. Lee JK, Stark WJ. Anesthetic keratopathy after photorefractive keratectomy. J Cataract Refract Surg. 2008;34:1803e1805. 53. Yagci A, Bozkurt B, Egrilmez S, et al. Topical anesthetic abuse keratopathy: a commonly overlooked health care problem. Cornea. 2011;30:571e575. 54. Rosenwasser GO, Holland S, Pflugfelder SC, et al. Topical anesthetic abuse. Ophthalmology. 1990;97:967e972. 97 Ophthalmology Volume 130, Number 1, January 2023 55. Taylor KR, Caldwell MC, Payne AM, et al. Comparison of 3 silicone hydrogel bandage soft contact lenses for pain control after photorefractive keratectomy. J Cataract Refract Surg. 2014;40:1798e1804. 56. Taylor KR, Molchan RP, Townley JR, et al. The effect of silicone hydrogel bandage soft contact lens base curvature on comfort and outcomes after photorefractive keratectomy. Eye Contact Lens. 2015;41:77e83. 57. AlDahash F, AlAmeer A, Hussain OB, et al. Effect of bandage contact lens exchange on pain and healing after photorefractive keratectomy-a randomized control trial. Eye Contact Lens. 2021;47:113e117. 58. Fujishima H, Yagi Y, Toda I, et al. Increased comfort and decreased inflammation of the eye by cooling after cataract surgery. Am J Ophthalmol. 1995;119:301e306. 59. Guillot X, Tordi N, Laheurte C, et al. 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Pereira VBP, Torriceli AAM, Garcia R, et al. Codeine plus acetaminophen improve sleep quality, daily activity level, and food intake in the early postoperative period after photorefractive keratectomy: a secondary analysis. Arq Bras Oftalmol. 2021;84:45e50. 65. Ibach MJ, Shafer BM, Wallin DD, et al. The effectiveness and safety of dextenza 0.4 mg for the treatment of postoperative inflammation and pain in patients after photorefractive keratectomy: The RESTORE Trial. J Refract Surg. 2021;37:590e594. 66. Shetty R, Dalal R, Nair AP, et al. Pain management after photorefractive keratectomy. J Cataract Refract Surg. 2019;45:972e976. 98 67. Bagherian H, Zarei-Ghanavati S, Momeni-Moghaddam H, et al. Masked comparison of two silicone hydrogel bandage contact lenses after photorefractive keratectomy. Cont Lens Anterior Eye. 2020;43:244e249. 68. Duru Z, Duru N, Ulusoy DM. Effects of senofilcon A and lotrafilcon B bandage contact lenses on epithelial healing and pain management after bilateral photorefractive keratectomy. Cont Lens Anterior Eye. 2020;43:169e172. 69. Duru N, Altunel O, Sirakaya E, Kucuk B. Comparison of the balafilcon A and samfilcon A lenses on postoperative pain control and epithelial healing time after photorefractive keratectomy: a contralateral eye study. Lasers Med Sci. 2020;35: 1955e1960. 70. Eliacik M, Erdur SK, Gulkilik G, et al. Compare the effects of two silicone-hydrogel bandage contact lenses on epithelial healing after photorefractive keratectomy with anterior segment optical coherence tomography. Cont Lens Anterior Eye. 2015;38:215e219. 71. Grentzelos MA, Plainis S, Astyrakakis NI, et al. Efficacy of 2 types of silicone hydrogel bandage contact lenses after photorefractive keratectomy. J Cataract Refract Surg. 2009;35: 2103e2108. 72. Mohammadpour M, Amouzegar A, Hashemi H, et al. Comparison of lotrafilcon B and balafilcon A silicone hydrogel bandage contact lenses in reducing pain and discomfort after photorefractive keratectomy: a contralateral eye study. Cont Lens Anterior Eye. 2015;38:211e214. 73. Mohammadpour M, Heidari Z, Hashemi H, Asgari S. Comparison of the lotrafilcon B and comfilcon A silicone hydrogel bandage contact lens on postoperative ocular discomfort after photorefractive keratectomy. Eye Contact Lens. 2018;44(Suppl 2):S273eS276. 74. Mukherjee A, Ioannides A, Aslanides I. Comparative evaluation of comfilcon A and senofilcon A bandage contact lenses after transepithelial photorefractive keratectomy. J Optom. 2015;8:27e32. 75. Razmjoo H, Abdi E, Atashkadi S, et al. Comparative study of two silicone hydrogel contact lenses used as bandage contact lenses after photorefractive keratectomy. Int J Prev Med. 2012;3:718e722. 76. Yuksel E, Ozulken K, Uzel MM, et al. Comparison of samfilcon A and lotrafilcon B silicone hydrogel bandage contact lenses in reducing postoperative pain and accelerating reepithelialization after photorefractive keratectomy. Int Ophthalmol. 2019;39:2569e2574.