Photorefractive keratectomy (PRK) is a common procedure to correct refractive error safely and effectively.1–3 However, the number of patients who have PRK remains lower than the number of those who have laser in situ keratomileusis.4 The 2 main reasons for this are slower visual recovery and discomfort in the immediate postoperative period after PRK.4,5 Since the procedure’s inception, considerable advances have been made to improve patient comfort during recovery after PRK.
The mechanism of pain after PRK is multifactorial.6 The potential targets for pain relief are, therefore, numerous and various analgesic strategies have been developed over the years. A bandage contact lens (BCL), for example, is effective in improving postoperative comfort by preventing lid movement over the abraded cornea and reducing stimulation of the nerve fibers sensitive to mechanical stimulation.7,8 However, a BCL is not enough to eliminate pain in most patients.7,9 The inflammatory cascade initiated after surgery generates inflammatory mediators that stimulate the nerves sensitive to chemical stimulation and also lower the sensitivity threshold of other types of nerve fibers.10,11 Even minor stimulation of the nerve endings in an inflamed tissue results in more discomfort than similar stimulation in a noninflamed tissue.12
During PRK, the inflammatory mediators are released from the disrupted corneal epithelial cells, keratocytes, and the inflammatory cells migrating into the cornea.10 They activate nerve fibers directly or indirectly. Some bind directly to the voltage-gated ion channels on the nerve fibers and cause an influx of charged molecules into the cells, resulting in the generation of action potential that leads to neuronal firing.8 Other inflammatory mediators bind to special molecules embedded in the terminal membranes of all nociceptors, called transducers. Activated transducers then activate the voltage-gated ion channels in the nerve membranes.13 The intensity of stimuli needed to activate transducers during the first 12 to 48 hours after PRK is lower than the intensity needed to activate transducers in intact corneas.11 Cryotherapy with a frozen Weck-Cel cellulose sponge (Beaver Visitec) soaked in balanced salt solution (“frozen popsicle”) applied immediately before and after PRK has been shown to decrease postoperative pain.A,B Cryotherapy reduces pain by several mechanisms, including vasoconstriction and reduction of inflammatory cell migration into the operative site.14
Once the nerve signal is initiated, it is propagated to the somatosensory cortex of the brain, where it is perceived as pain.15 In addition to the somatosensory cortex, multiple brain areas that are associated with emotion have been shown to be activated during a painful stimulus.16
Currently used analgesic medications after PRK include nonsteroidal antiinflammatory drugs (NSAIDs), anesthetics, opiates, acetaminophen, and para-aminobenzoic acid analogues (gabapentin and pregabalin). These classes of analgesics aim at a wide variety of targets, including peripheral corneal nerves, inflammatory mediators in the cornea and the surrounding eye areas, and targets within the central nervous system. Although many studies to evaluate efficacy and safety of the individual drugs have been published to date, to our knowledge, there has not been a systematic review of all the prospective randomized trials of medications used to treat pain after PRK. We performed such a review with the goal of answering the following questions: What is the efficacy and safety of medications in the various classes of analgesics? Are there differences in efficacy and safety between drugs in the same class? Are there differences in the efficacy and safety between the classes of analgesics? Is the effect additive when different classes of analgesics are used together?
Materials and methods
The search engine Pubmed was used to search the literature. The search was restricted to English language reports published between January 1, 1993, and September 1, 2013. The following search terms were used: photorefractive keratectomy, PRK, advanced surface ablation, excimer laser surface ablation, and all of those terms followed by “AND” the following: pain, pain relief, analgesia, pain relief medications, nonsteroidal antiinflammatory drugs, anesthetics, gabapentin, pregabalin, opiates, sumatriptan, triptans. The reference list of each citation was also examined for relevant articles.
Our search yielded 30 studies. All prospective randomized trials with active- or placebo-controlled treatment groups were included in the review. Both masked and open-label studies were eligible for the review. Twenty-three reports were selected for data extraction.
Data Extraction and Analysis
Data from the 23 studies were extracted using a standardized form. Two reviewers (K.M., E.G.F) performed data extraction and assessment of study quality. Results were compared, and the reviewers resolved any discrepancies through discussion. The following data were collected: study design and size (the number of eyes in each study group and placebo group, where applicable), frequency and duration of administration of study medications and controls, additional medications administered before and after surgery, whether a BCL was used postoperatively, whether the eye was patched, pain assessment methods, efficacy of pain relief (P values), and reported adverse effects.
Assessment of Study Quality
The risk for bias in the included studies was assessed using the method developed by Jadad et al.17 A Jadad score is calculated using 7 questions: Was the study described as randomized (yes = +1, no = 0)? Was the method used to generate the sequence of randomization described and appropriate (yes = +1, no = 0)? Was the method used to generate randomization inappropriate (yes = −1, no = 0)? Was the study described as double blind (yes = +1, no = 0)? Was the method of double blinding described and appropriate (yes = +1, no = 0)? Was the method of blinding inappropriate (yes = −1, no = 0)? Was there a description of withdrawals and dropouts (yes = +1, no = 0). The range of possible scores was 0 (high bias) to 5 (low bias).
Three studies of topical anesthetics used after PRK were identified (Table 1).18–20 Three types of anesthetics were studied: tetracaine 1.0%, proparacaine 0.05%, and bupivacaine 0.75%.
Both tetracaine 1.0% and proparacaine 0.05% were more effective than placebo control in relieving pain after PRK.18,20 Tetracaine 1.0% was marginally more effective than bupivacaine 0.75%.19
The study by Verma et al.20 reported delayed reepithelialization at 24 hours postoperatively in patients using tetracaine 1.0% every 30 minutes while awake for the first 24 hours. The rate of epithelialization caught up at the subsequent visits. In another study by Verma et al.,19 the eyes in both tetracaine and bupivacaine groups epithelialized by 72 hours postoperatively. The study by Shaninian et al.18 reports the mean number of days to reepithelialization was higher in patients using proparacaine 0.05% than in those using placebo, although the difference was not statistically significant. Patients in the proparacaine 0.05% group used a total of 34 drops per eye during the 7 days of study duration (mean 4.86 drops per day).
Topical Nonsteroidal Antiinflammatory Drugs
The results of 17 studies published since 1993 are summarized in Table 2.21–37 Six types of NSAIDs were studied: diclofenac 0.1% (Voltaren), bromfenac 0.09% (Xibrom), ketorolac 0.4% and 0.5% (Acular LS and Acular, respectively), nepafenac 0.1% and 0.03% (Nevanac), flurbiprofen 0.03% (Ocufen), and indomethacin 0.1% (not currently available commercially).
Five studies initiated a topical NSAID before PRK.21,22,28,35,36 All other studies initiated the drug after PRK. In all but the study by Caldwell and Reilly,24 the drops were started immediately after the completion of surgery. The drugs were continued for 1 to 7 days after surgery. In most studies, the drugs were used for 3 days after surgery, 3 to 4 times a day.
Nine studies compared NSAIDs and a vehicle control.21,22,24,29,30,31,33,35,37 The NSAIDs studied were nepafenac, ketorolac 0.4% and 0.5%, diclofenac, flurbiprofen, and indomethacin. All drugs were more effective than the vehicle control in relieving pain after PRK. Six of the studies compared the efficacy of diclofenac with that of a vehicle control.21,22,30,33,35,37 All found diclofenac to be more effective than placebo except the study by Assouline et al.,33 which did not find a difference between the drug and the placebo. In the Assouline et al. study, diclofenac was instilled after PRK and the eyes were patched. In the other studies of diclofenac versus placebo, the eyes were pretreated with diclofenac before surgery and then patched or not patched and instead covered with a BCL or nothing at all.21,22,30,35,37
Razmju et al.21 and Mohammadpour et al.22 investigated the analgesic effect of topical NSAIDs administered preoperatively on pain after PRK. In the former study, topical diclofenac and ketorolac 0.5% were more effective than placebo in relieving pain on postoperative days 1 and 2, although the effect was less pronounced on postoperative day 2. In the latter study, diclofenac was more effective in relieving pain on postoperative day 1 but not on postoperative day 2. In the former study, an NSAID was given only once before surgery. In the latter study, patients also used the medication for 2 days following the surgery.
When different NSAIDS were compared, the efficacy results varied between the studies. Most notably, the efficacy data were mixed when nepafenac was compared with ketorolac 0.4%. Some studies found nepafenac to be similar to ketorolac 0.4% in relieving pain after PRK.26 Others found it to be better.25 Yet others found it to be worse.27 In the latter study, the authors placed the NSAID drops on the cornea immediately after PRK and before the BCL placement, whereas in the other 2 studies, the drop was placed after the BCL. In addition, the study by Trattler and McDonald27 was the only one that reported initiating cyclosporine 0.05% drops and placing punctual plugs before the surgery. Cyclosporine was continued until the BCL was removed.
Colin and Paquette28 reported nepafenac 0.1% to be more effective than 0.03% at 3 hours after surgery. At all other postoperative times, the efficacy of the 2 concentrations was similar and was also similar to that of diclofenac. Two studies found flurbiprofen to be more effective than diclofenac.30,32 One found flurbiprofen was also more effective than ketorolac 0.5% and indomethacin.30 Both studies found the efficacy of ketorolac 0.5% to be similar to that of indomethacin.30,32 Weinstock et al.36 found mean pain scores to be lower in patients receiving ketorolac 0.5% than in patients receiving diclofenac, although maximum pain scores and the use of escape medications were similar.
Two studies compared bromfenac and ketorolac 0.4%.23,25 Both found the drugs to be equally effective in relieving pain after PRK.
Razmju et al.21 compared the efficacy of preoperative diclofenac and ketorolac 0.5% in relieving pain after PRK. The drugs were equally effective.
Thirteen of 17 studies reported adverse effects.22–33,35,37 These ranged from mild burning/stinging/foreign-body sensation on instillation of the drop to an occasional small epithelial defect or an infiltrate to delayed reepithelialization and corneal haze. One study reported no adverse effects.22 Two studies did not report the presence or absence of adverse effects.34,36
Of the NSAIDs studied, nepafenac had the most reported adverse effects. Caldwell and Reilly24 reported that epithelial defect was significantly larger in nepafenac-treated eyes than in placebo eyes on postoperative day 2. Trattler and McDonald27 had to halt the nepafenac versus ketorolac 0.4% study after treating only 7 patients (out of 60 planned) because of slower reepithelialization and greater haze scores in the nepafenac eyes. Donenfeld et al.26 reported 1 case of epithelial defect in the nepafenac group and none in the ketorolac 0.4% group. Colin and Paquette28 reported ocular discomfort in a patient receiving nepafenac 0.1% and a corneal infiltrate in a patient receiving 0.03%. However, in the study by Durrie et al.,25 reepithelialization was faster in the nepafenac group than in the ketorolac 0.4% group, although the difference was not statistically significant.
Durrie et al.,25 also showed that reepithelialization was slowest in the bromfenac group compared with the nepafenac and ketorolac 0.4% groups. Sher et al.,23 however, showed reepithelialization in the bromfenac group to be similar to that in the ketorolac 0.4% group. In the former study, bromfenac was used 3 times a day and in the latter study, twice a day. Delayed reepithelialization was noted in patients receiving ketorolac 0.4%,29 ketorolac 0.5%,30,31 indomethacin,30 and diclofenac.28,30,33,37
Infiltrates were reported in 2 patient using ketorolac 0.4%,26,29 1 patient using nepafenac 0.03%,28 and 1 patient using diclofenac.37 Infiltrates were also reported in 2 patients receiving placebo.29,37
Mild transient ocular burning after drop instillation was reported in patients using ketorolac 0.4%,26 nepafenac 0.1%,26,28 diclofenac 0.1%, and flurbiprofen 0.03%.32 The study by Vetrugno et al.30 reported itching on instillation of ketorolac 0.5% and indomethacin, but these drops contained preservatives unlike the flurbiprofen and diclofenac drops in the same study.
Gabapentin and Pregabalin
Three prospective randomized trials have been published to date on the use of oral gabapentin (Neurontin) for pain relief after PRK (Table 3).38–40 All 3 trials compared gabapentin with a placebo control. The study by Pakravan et al.38 also compared gabapentin with pregabalin (Lyrica) and with a placebo. In each of the 3 studies, patients received a different dose of gabapentin. In the Lichtinger et al. study,40 patients received 300 mg of gabapentin the day before surgery, 300 mg on the day of the procedure, and 900 mg/day for the subsequent 3 days. In the Kuhnle et al.39 study, patients received 900 mg of gabapentin/day for 2 days prior to surgery followed by 900 mg/day for 4 days after surgery. In the Pakravan et al. study,38 the patients were treated with 900 mg/day for 3 days after surgery.
The Pakravan et al.38 and Lichtinger et al.40 studies found gabapentin to be more effective than placebo in relieving pain after PRK. Kuhnle et al.39 did not find it to be more effective on the Visual Analog Scale of pain intensity, but the study group patients reported lower consumption of narcotics on postoperative day 1 than the placebo group patients.
The 3 studies had major design differences. In the Lichtinger et al. study,40 postoperative medications did not include analgesics other than gabapentin in the study group. In the Pakravan et al. study,38 patients were allowed to take acetaminophen/codeine as needed. In the Kuhnle et al. study,39 patients could take not only oxycodone/acetaminophen but also topical and oral NSAIDs for breakthrough pain. While this study reported patients in the gabapentin group using less oral narcotic than the patients in the placebo group, the study did not include comparison data for the use of topical or oral NSAIDs.
Pregabalin was more effective than placebo and as effective as gabapentin in relieving pain after PRK.38
No corneal side effects were reported in any study. Lichtinger et al.40 compared rates of reepithelialization between the study group and the control group and found no statistically significant difference. Nausea was reported in 1 patient in the Kuhnle et al. study39 and 3 patients in the gabapentin group in the Pakravan et al. study.38 Lichtinger et al.40 found the severity of systemic symptoms such as dizziness, drowsiness, headache, and gastrointestinal symptoms to be similar in the study group and the control group.
One trial compared the efficacy and safety of topical morphine 0.5% and the placebo control in patients after PRK.41 Forty patients were randomized to receive the study medication (20 patients) or the vehicle control (20 patients). The drops were initiated following the procedure and used every 2 hours on the day of the procedure, followed by 4 times a day for the subsequent 3 days. The patients did not receive topical NSAIDs or topical anesthetics. Oral hydrocodone/acetaminophen (5 mg/500 mg) was allowed as needed.
Patients in the topical morphine groups reported less pain on pain assessment questionnaires and reduced consumption of oral narcotics (P<.05).
No difference in reepithelialization was noted between the study group and the control group. No adverse corneal or systemic effects were reported.
Safety and Efficacy Comparison of Drugs in Different Classes of Analgesics
Studies that fit the criteria for this review did not include direct comparison of drugs in different classes of analgesics. Study designs were also different enough, especially in the methods used to assess pain relief, to preclude comparison of treatment outcomes between medications in different studies. However, all classes of medications studied included data comparing the efficacy and safety of medications with those of the placebo control. The strength of the P values comparing medications with the placebo control were used to determine whether there are trends suggesting differences between the medications. Table 4 summarizes analgesic efficacy (P values) and adverse effects of medications compared with those of the placebo control. Tetracaine 1.0% and nepafenac 0.1% had the lowest P values when their analgesic efficacy was tested against the placebo control (P<.0001).20,24 Tetracaine 1.0% showed the most significant delay in epithelialization when tested against placebo (P<.0001) compared with other topical medications tested against placebo.20
Prospective randomized studies of medications used to treat pain after PRK demonstrate that efficacy and safety of drugs within the same class of analgesics tend to be similar. The most studies of post-PRK analgesia published to date have been on the use of topical NSAIDs. Inflammation plays a key role in causing pain after PRK.10 The inflammatory pathway is, therefore, an important target for analgesia. All NSAIDs block a proinflammatory enzyme, cyclooxygenase (COX), which is embedded in cell membranes.42 Cyclooxygenase performs many functions, some that are necessary for normal cell function and some that facilitate inflammation by converting arachidonic acid released from disrupted cell membranes into prostaglandins. There are 2 forms of COX: COX-1 and COX-2.43 Cyclooxygenase-1 is present in most cell membranes under normal uninflamed conditions. Cyclooxygenase-2 is also present in normal cells in some organs but is mostly synthesized by cells in response to inflammation.44 All NSAIDs target both isoforms of the enzyme. Some have been shown to have greater affinity for COX-1; others bind COX-2 better. Some are delivered to the surface of the eye in 1 form and are then converted by the eye into another one. Some are more likely to penetrate cell membranes whereas others are less so.45 But do the NSAIDs differ in their ability to relieve pain after PRK? While there were some differences in outcomes, overall the efficacy of drugs was more similar than different, especially in the studies performed in the past 10 years. Bromfenac was found to be similar to ketorolac. Ketorolac was similar to nepafenac, which was similar to diclofenac. These results are consistent with the published data on the efficacy of systemic NSAIDs in relieving acute pain. Ong et al.46 compiled the efficacy data from published studies on all systemic analgesics, including all NSAIDs, opiates, and others and compared the efficacy of the drugs in relieving acute pain. While there was dose-dependent response for each of the NSAIDs, the efficacy scores for systemic ketorolac, bromfenac, diclofenac, and naproxen were similar. We were, therefore, not surprised when we observed the tendency for topical NSAIDs to be more similar than different in relieving pain after PRK in the published trials.
Most of the studies analyzed analgesic efficacy of NSAIDs administered postoperatively. Two studies evaluated the effect of pretreatment with topical NSAIDS on postoperative pain.21,22 Both found pretreatment effective in relieving pain after surgery even when patients received no postoperative analgesic other than acetaminophen.
Efficacy of different topical anesthetics was compared in 1 study.19 In this study, tetracaine was similar to bupivacaine in relieving pain after PRK. Efficacy of different gamma-aminobutyric acid analogues, gabapentin and pregabalin, were compared in the study by Pakravan et al.38 The efficacy of these drugs were similar.
Studies that met the criteria for this review did not include direct comparison of treatment outcomes between drugs in different analgesic classes. Study designs were also different enough to preclude comparison of pain relief scores of drugs from different studies. To determine whether the efficacy of drugs in different analgesic classes tends to be similar or different, we compared P values of analgesic efficacy when the drugs were tested against placebo. Overall, P values tended to be similar between drugs in different analgesic classes. Tetracaine 1.0% and nepafenac 0.1% had the smallest P values, suggesting the most statistically significant analgesic effect when tested against placebo compared with other drugs.20,24 Considering the limitations of such an indirect comparison, future studies can be considered that directly compare the effect of these drugs to other analgesics.
When different classes of analgesics are used in combination, the effect may or may not be additive.46 A study by Pakravan et al.38 found both gabapentin and pregabalin to be effective when added to acetaminophen-codeine postoperatively. A study by Kuhnle et al.39 did not see significant improvement in pain when patients added oral gabapentin to topical NSAIDs, oral NSAIDs, and hydrocodone bitartrate and acetaminophen (Vicodin); however, the consumption of hydrocodone bitartrate and acetaminophen was decreased.39 Gabapentin has been shown to decrease the use of opiates postoperatively, although the reason for this is unclear.47 The 2 types of drugs may be synergistic due to their separate action sites. Alternatively, gabapentin may decrease postoperative opiate requirement by preventing development of opioid tolerance. When added to the postoperative regimen of stronger opiates, such as bitartrate and acetaminophen, for example, pretreatment with a single 1200 mg dose should be considered to achieve significant pain relief. A literature review of preoperative gabapentin used as an adjunct to other analgesics for pain management after nonocular surgery showed that a single preoperative dose of 1200 mg of gabapentin is the most effective in reducing postoperative pain.47 Multiple dosing with gabapentin preoperatively and continued dosing postoperatively, as done in the Kuhnle et al.39 study, did not reduce Visual Analogue Scale scores in patients after nonocular surgery. The study by Cherry,9 which did not fit the inclusion criteria for this review, found that patients experienced less pain when they used both tetracaine 1.0% and diclofenac 0.1% than patients who used each medication alone. Some data in that study were retrospective. The study was, therefore, not included in this review.
Reported side effects were rare. The most common side effect of topical anesthetics and topical NSAIDs was delayed reepithelialization. Two of the 3 studies comparing topical anesthetics with a placebo control found that patients using the drug reepithelialized slower than those using the placebo.18,20 In 1 study, however, the difference was not statistically significant.18 In this study, proparacaine 0.05% was used and it was used less frequently, between 4 and 5 times a day, on average. In the study with a statistically significant delay in reepithelialization, tetracaine 1.0% was used and it was used more frequently, every 30 minutes.20 In fact, tetracaine 1.0% had the most statistically significant P value of all the topical analgesics when rates of corneal reepithelialization were tested against the rates with the placebo, suggesting that it could be the most toxic to the epithelium. Topical anesthetics have, in fact, been shown to disrupt epithelial cell motility and cause keratocyte toxicity.48,49 Toxic keratopathy after PRK has been reported during frequent and/or prolonged use of the medication.50,51 Based on the results of the studies in this review, patients who are prescribed a topical anesthetic after PRK may be advised to not exceed 5 drops a day for a maximum of 7 days. Frequent use of topical anesthetic, especially tetracaine, may have to be avoided.
The most common side effect of topical NSAIDs was also delayed reepithelialization. Eleven of 17 studies found delayed reepithelialization in eyes treated with NSAIDs.24–31,33,35,37 Epithelium eventually healed in all eyes without sequelae in all but 1 study.27 In the Trattler and McDonald study,27 7 eyes treated with nepafenac not only had significantly delayed reepithelialization compared with eyes receiving ketorolac, but also had an increased incidence of corneal haze that resulted in loss of corrected visual acuity. Other studies that compared nepafenac and ketorolac found no significant difference in epithelial healing between the 2 drugs.25,26 There were 3 significant differences between the Trattler and McDonald27 study and the other 2 studies: The drug was applied before the BCL placement, patients used cyclosporine 0.05% drops concomitantly with the drug, and patients had punctual plugs. All these factors may have increased the amount and/or bioavailability of the drug to the cornea.
Nepafenac, like all other NSAIDs, inhibits both COX-1 and COX-2 isotypes of enzyme COX. Unlike other NSAIDs, however, nepafenac has significantly higher affinity for COX-1 than COX-2.52 It has been demonstrated that COX-1 is primarily responsible for normal functioning of the cells, whereas COX-2 is the primary mediator for ocular inflammation.45 When nepafenac penetrates the cornea and enters the eye, it is converted to amphenac, which has a greater affinity for COX-2. Although the drug is in the nepafenac form on the surface of the cornea, it blocks COX-1 more than it blocks COX-2. Perhaps if the concentration of nepafenac on the cornea is too high, the inhibition of COX-1 is too great and normal cell functioning is disrupted. This hypothesis may explain why the adverse reaction was greater in the eyes treated with nepafenac than in the eyes treated with ketorolac in the Trattler and McDonald study.27
The incidence of corneal infiltrates was extremely rare. None of the patients who received topical anesthetics developed infiltrates. Only 5 patients in the 17 studies of topical NSAIDs developed small infiltrates presumed to be sterile.26,28,29,37 None were described to have resulted in adverse vision outcomes. Three of the patients with infiltrates were in studies that reported no steroid use concomitant with the NSAID.28,29
The study of topical morphine showed no delay in reepithelialization and no adverse corneal events.41 This was not surprising because unlike the anesthetics and the NSAIDs, topical opiates bind to specific opiate receptors present on only corneal nerves and inflammatory cells, not on other corneal cells.53 Further studies are indicated to evaluate the analgesic potency of topical morphine compared with the more commonly used analgesics after PRK.
In conclusion, currently used analgesics are safe and effective in improving postoperative comfort after PRK. The safety and efficacy of the drugs tend to be similar. Tetracaine 1.0% and nepafenac 0.1% tend to be more effective than other analgesics compared with a placebo; however, tetracaine tends to cause the most significant delay in corneal epithelialization. Its use may, therefore, have to be limited, especially in conjunction with other drugs such as topical NSAIDs, which can also be associated with corneal toxicity. Although different classes of analgesics are often used together to treat post-PRK pain, the data to support safety and efficacy of such use are minimal. Future studies may be considered to investigate whether concomitant use of different classes of medications is more effective and as safe as using each of the drugs alone. Finally, although the side effects are rare, they could be eliminated entirely by developing drugs that will target receptors specific to peripheral corneal nerves, avoiding the interaction with other corneal cells and avoiding systemic effects.
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