Efficacy and safety of pain relief medications after photorefractive keratectomy: review of prospective randomized trials.

REVIEW/UPDATE

Efficacy and safety of pain relief medications after photorefractive keratectomy: Review of prospective randomized trials Ella G. Faktorovich, MD, Karishma Melwani, BA

The objective of this review was to provide a comprehensive overview and comparison of results from all prospective randomized trials published to date of medications used to treat pain after photorefrative keratectomy (PRK). A PubMed database search revealed 23 prospective and randomized studies. They included the following classes of medications: nonsteroidal antiimflammatory drugs (NSAIDs), anesthetics, opiates, acetaminophen, gabapentin, and pregabalin. The studies found that although the efficacy of drugs tended to be similar, tetracaine 1% and nepafenac 0.1% tended to have the most analgesic effect. Delayed corneal reepithelialization was a common side effect of both topical anesthetics and topical NSAIDs. Tetracaine 1% resulted in the most significant delay in reepithelialization when tested against placebo control compared with other topical medications tested against placebo. Concomitant use of topical NSAIDs and topical anesthetics, especially tetracaine, may have to be avoided to minimize the risk for delayed corneal healing. Financial Disclosure: Neither author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1716–1730 Q 2014 ASCRS and ESCRS

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,

Submitted: September 15, 2013. Final revision submitted: January 29, 2014. Accepted: February 3, 2014. From the Refractive and Corneal Surgery, Pacific Vision Institute, San Francisco, California, USA. Corresponding author: Ella G. Faktorovich, MD, Refractive and Corneal Surgery, Pacific Vision Institute, One Daniel Burnham Court, San Francisco, California 94109, USA. E-mail: ella@ pacificvision.org.

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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 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2014.08.001

REVIEW/UPDATE: EFFICACY AND SAFETY OF PAIN RELIEF MEDICATIONS AFTER PRK

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 Search Strategy

Selection Criteria 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. Twentythree 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 Z C1, no Z 0)? Was the method used to generate the sequence of randomization described and appropriate (yes Z C1, no Z 0)? Was the method used to generate randomization inappropriate (yes Z 1, no Z 0)? Was the study described as double blind (yes Z C1, no Z 0)? Was the method of double blinding described and appropriate (yes Z C1, no Z 0)? Was the method of blinding inappropriate (yes Z 1, no Z 0)? Was there a description of withdrawals and dropouts (yes Z C1, no Z 0). The range of possible scores was 0 (high bias) to 5 (low bias).

LITERATURE REVIEW Topical Anesthetics 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 Efficacy

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

Safety

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.

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Table 1. Topical anesthetics after PRK. Study*

Agent

Frequency and Duration of Administration

Study Size

Additional Medications

Shahinian18

Proparacaine 0.05% vs placebo

25 eyes proparacaine/ 23 eyes placebo (34 patients)

As needed 7 days (on average, 34 drops/eye for study group vs 17 drops/eye for placebo group/study duration)

Preop : NA Postop: BCL, diclofenac 0.1% QID 1 day; tobramycin 0.3%, dexamethasone 0.1% QID 7 days; acetaminophen/hydrocodone prn

Verma19

Tetracaine 1% vs bupivacaine 0.75%

19 eyes tetracaine/ 19 eyes bupivacaine (38 patients)

Q 30 mins 24 hr postop

Preop: pilocarpine 4% Postop: Coproxamol (paracetamol/ dextropropoxyphene) 2 tabs PO Q8 hr 2 days; chloramphenicol 0.5% Q6 hr 7 days

Verma20

Tetracaine 1% vs placebo

22 eyes tetracaine/ 22 eyes placebo (44 patients)

Immediately preop; Q 30 min while awake 24 hr postop

Preop: pilocarpine 4% Postop: Coproxamol (paracetamol/ dextropropoxyphene) 2 tabs PO Q8 hr 2 days; chloramphenicol 0.5% Q6 hr 7 days

BCL Z bandage contact lens; NA Z information not available; NRS Z numerical rating scale; NS Z not statistically significant (P!.05 was considered statistically significant pain relief); PRK Z photorefractive refractive keratectomy; VAS Z visual analog scale All studies were double-masked. *First author

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

Efficacy

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,


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Table 1. (Cont.)

Efficacy

NRS 0-10; length of time pain relief lasted; how helpful were the drops; use of escape medication

P!.001 to P!.002

Average number of days to reepithelialization 3.48 in proparacaine group vs 3.13 in placebo group (difference NS)

5

VAS 0-10

PZ.05

None

4

VAS 0-10

P!.0001

Delayed closure of epithelial defect in tetracaine group at 24 hr postop

4

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. Safety Thirteen of 17 studies reported adverse effects.22–33,35,37 These ranged from mild burning/ stinging/foreign-body sensation on instillation of the

Adverse Effects

Quality Score

Pain Measurements

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


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Table 2. Topical NSAIDs after PRK. Frequency and Duration of Administration

Study*

Agent

Study Size

Razmju21

Diclofenac 0.1% vs placebo; ketorolac 0.5% vs placebo

47 eyes diclofenac/47 eyes placebo (47 patients); 36 eyes ketorolac/36 eyes placebo (36 patients)

30 minutes preop

Mohammadpour22

Diclofenac 0.1% vs placebo

70 eyes diclofenac/70 eyes placebo (70 patients)

2 hr preop study drop in 1 eye, placebo drop in the other eye; study drops OU immediately postop, followed by study drops OU QID 2 days postop

Sher23

Bromfenac 0.09% vs keterolac 0.4%

97 eyes bromfenac/102 eyes ketorolac (87 patients pairedeye and 62 patients unilateral)

Immediately postop; keterolac QID or bromfenac BID until reepithelializion (POD4-5)

Caldwell24

Nepafenac 0.1% vs placebo

66 eyes nepafenac/66 eyes placebo (66 patients)

TID 5 days postop

Durrie25

Nepafenac 0.1% vs ketorolac 0.4% vs bromfenac 0.09%

30 eyes nepafenac/14 eyes ketorolac/14 eyes bromfenac (29 patients)

Immediately postop; TID 7 days

Donnenfeld26

Nepafenac 0.1% vs ketorolac 0.4%

40 eyes nepafenac/40 eyes ketorolac (40 patients)


Trattler27

Nepafenac 0.1% vs ketorolac 0.4%

7 eyes nepafenac/7 eyes ketorolac (14 patients)



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Table 2. (Cont.) Additional Medications Preop: tetracaine 0.5% OU Postop: 0.02% MMC, BCL, ciprofloxacin QID, betamethasone Q3 hr, acetaminophen 500 mg QD

Pain Measurements

Efficacy

VAS (0 to 10); CS (none, mild, P!.05 diclofenac vs placebo; moderate, severe); use of P!.05 ketorolac vs placebo; escape medications NS diclofenac vs ketorolac POD1 and POD2

NRS (0 to 10) Preop: tetracaine 0.5% OU Postop: BCL, chloramphenicol and betamethasone QID

Adverse Effects

Quality Score

None

5

PZ.018 at POD1, NS at POD2 None

4

Preop: topical 0.5% proparacaine OU Postop: 0.02% MMC in some patients, chilled BSS, BCL, prednisolone acetate 1.0%, gatifloxacin 0.3% QID

VAS (0 to 10)

NS

1 case of infectious keratitis

2

Postop: BCL, moxifloxacin TID, fluorometholone QID, oral diphenhydramine 50 mg prn and oxycodone/ acetaminophen prn

VAS (0 to 10)

P!.0001 on POD1; P!.0005 on POD2; NS on POD3

Epithelial defect larger in nepafenac group than placebo group on POD 2 (PZ.0014); all eyes healed by POD4

5

VAS (0 to 10) Preop: moxifloxacin or gatifloxacin, tropicamide 1.0%, phenylephrine 2.5%, tetracaine, frozen BSS Postop: BCL, moxifloxacin 0.5% in nepafenac group TID, gatifloxacin 0.3% in ketorolac and bromfenac groups TID, prednisolone acetate 1.0% QID, hydrocodone 5 mg/500 acetaminophen prn

P!.05 in nepafenac eyes on POD1 and 3; NS in ketorolac and bromfenac eyes on POD 1 but P!.05 on POD3

Reepithelialization in bromfenac group took longer than in nepafenac and ketorolac groups (P!.05); reepithelialization in nepafenac vs ketorolac NS

4

VAS (1 to 10) Preop: proparacaine 1.0% Postop: BCL, moxifloxacin 0.5% TID, prednisolone acetate 1.0% TID, hydrocodone 5 mg/ 500 acetaminophen prn

NS

Irritation and burning after drop instillation lower in nepafenac group on POD3 (P!.05); 1 case of keratitis (ketorolac), 1 case of a small epithelial defect (nepafenac)

4

Preop: Vitamin C 1 gm NRS (0 to 10) PO 1 wk, cyclosporine 0.05% OU BID 1-3 weeks, punctual plugs, proparacaine, ice cold BSS Postop: gatifloxacin 0.03%, prednisolone acetate 1.0%, NSAID drop, BCL; gatifloxacin 0.03% TID, prednisolone acetate 1.0% TID

PZ.046 in ketorolac eyes vs nepafenac

Study halted after 7 patient enrollment (vs 60 planned) due to greater haze score in nepafenac group (P!.05); slower reepithelialization in nepafenac group (7.9 G 2.1 days vs 5.7 G 1.1, but NS

3


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Table 2. Topical NSAIDs after PRK.

Study*

Agent

Study Size


Colin28

Nepafenac 0.03% vs nepafenac 0.1% vs diclofenac 0.1%

20 eyes nepafenac 0.03%/20 eyes in nepafenac 0.1%/20 eyes diclofenac (60 patients)

1 hour preop, 1, 4, and 8 hr postop: QID on POD1

Solomon29

Ketorolac 0.4% vs placebo

150 eyes ketorolac/144 eyes placebo (294 patients)

Immediately postop; at 3 hours; Q4 hours on procedure day; QID on POD1-3

Vetrugno30

Diclofenac 0.1% vs flurbiprofen 0.03% vs ketorolac 0.5% vs indomethacin 0.1% vs placebo

25 eyes in each of the 5 groups (125 patients)

Immediately postop; QID

Rajpal31

Ketorolac 0.5% vs placebo

102 eyes ketorolac/98 eyes placebo (200 patients)

Immediately postop; QID 3 days

Appiotti32

Flurbiprofen 0.03% vs diclofenac 0.1%

16 eyes flurbiprofen/16 eyes diclofenac (16 patients)

Immediately postop; 6 /day on POD1-3; QID on POD4-7

Assoulin33

Indomethacin 0.1% vs diclofenac 0.1% vs placebo

39 eyes indomethacin/41 eyes diclofenac/40 eyes placebo (120 patients)

Immediately postop; QID 3 days

Frangouli 34

Indomethacin vs ketorolac 0.5%

60 eyes indomethacin/60 eyes ketorolac (120 patients)

N/A

Tutton35



1 hour and 30 minutes preop; immediately postop; Q2 to 5 hr 24 hr


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Table 2. (Cont.)


Pain Measurements

Postop: homatropine 1% for VAS (0 to 9) 45/60 patients; acetaminophen 500 mg po prn

Efficacy

P!.05 in nepafenac 0.1% eyes Corneal infiltrate in 1 patient in vs 0.03% at 3 hr postop; NS at nepafenac 0.03%, ocular all other times discomfort in 1 patient in nepafenac 0.1% group; reepithelialization slowest in diclofenac vs nepafenac 0.03% and 1.0%, but difference NS

NRS (0 to 4); incidence rate of P!.001 Postop: Ofloxacin QID; time to first no-pain report; use acetaminophen 300 mg with codeine 30 mg 1 tab Q4 hrs prn of escape medication

Preop: 0.4% oxybuprocaine hydrochloride Postop: ofloxacin QID BCL, then ofloxacin QID, ketorolac tromethamine, 10 mg po prn

Adverse Effects

McGill Pain Questionnaire; use P!.001 for all NSAID eyes vs of escape medication placebo; P!.001 in flurbiprofen eyes vs diclofenac, ketorolac, and indomethacin

Preop: Pilocar 1.0%, tetracaine NRS (0 to 6); use of escape medication 0.5% Postop: ofloxacin QID 3 D, mepergan fortis po prn

PZ.001

Quality Score 4

33/156 ketorolac patients vs 16/157 placebo patients with delayed reepithelialization, NS; 2 infiltrates in ketorolac (1 unrelated to treatment), 1 infiltrate in placebo

3

Longer reepithelialization in ketorolac, indomethacin, and diclofenac vs flurbiprofen and placebo (P!.001); itching in ketorolac and indomethacin patients (but these had preservatives)

3

Mean time to reepithelialization was 1/2 day longer in ketorolac group (PZ.001)

4

Preop: oxybuprocaine 0.4% Postop: BCL, ofloxacin 6 / day on POD1-3, then QID on POD4-7

Descriptor scale (0 to 7) and visual ordinal scales (0 to 9)

P!.05 for flurbiprofen eyes vs Mild and transient ocular diclofenac burning after instillation for both treatments

2

Preop: oxybuprocaine 0.4% Postop: patch, then Bacitracin eyedrops QID 5 days, acetaminophen 500 mg/ dextroproxyphen and lorazepam 1 mg prn

VAS (1 to 10)

PZ.05 for indomethacin eyes vs placebo and diclofenac on procedure day; NS on POD1 and 2

Delayed reepithelialization in diclofenac group

5

Postop: chloramphenicol ointment

VAS (0 to 10); McGill Pain Questionnaire; State Trait Anxiety Inventory; use of escape medications

NS

N/A

2

Preop: pilocarpine 1.0%, amethocaine 0.1% Postop: homatropine 2.0%, chloramphenicol 0.5%, patch, dihydrocodeine 10 mg/ paracetamol 500 mg po prn

VAS (0 to 10), CS (none, mild, PZ.012 moderate, severe); use of escape medication

Delayed reepithelialization in diclofenac group on POD1 (P!.05) but all eyes healed from 3 to 14 days postop

5


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Table 2. Topical NSAIDs after PRK.

Study*

Agent


Study Size

Weinstock36

Diclofenac 0.1% vs ketorolac 0.5%

51 eyes diclofenac/51 eyes ketorolac (102 patients)

1 hr and 1 min preop; immediately postop; Q4 hr

Sher37



Immediately postop; Q6 hr

BCL Z bandage contact lens; CS Z categorical scale; MMC Z mitomycin-C; NA Z information not available; NRS Z numerical rating scale; NS Z not statistically significant (P!.05 considered statistically significant pain relief); POD Z postoperative day; PRK Z photorefractive keratectomy; VAS Z visual analog scale All studies were double-masked except Sher37 (open label) and Appiotti32 (patient masked). *First author

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

Table 3. Oral gabapentin and pregabalin after PRK. Study*

Frequency, Dose, Duration of Administration

Agent

Study Size

Pakravan38

Gabapentin vs pregabalin vs placebo

50 patients gabapentin/50 patients pregabalin/50 patients placebo (150 patients)

Gabapentin 300 mg TID 3 days, pregabalin 75 mg TID 3 days

Kuhnle39

Gabapentin vs placebo

42 patients gabapentin/41 patients placebo (83 patients)

300 mg TID 2 days before procedure; then 300 mg TID 4 days postop

Lichtinger 40

Gabapentin vs placebo

20 patients gabapentin/20 patients placebo (40 patients)

300 mg the day before procedure; 300 mg on procedure day; 300 mg TID on POD1-3

BCL Z bandage contact lens; NS Z not statistically significant (P!.05 considered statistically significant pain relief); POD Z postoperative day; PRK Z photorefractive keratectomy; VAS Z visual analog scale All studies were double-masked. *First author


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Table 2. (Cont.)


Pain Measurements

Efficacy

CS (none, mild, moderate, Preop: proparacine 0.5%, severe); use of escape tobramycin, polytrim Postop: patch, diazepam 20 mg medication po, tobramycin and polytrim Q4 hours, acetaminophen 650 mg/ caffeine 30 mg/codeine 16 mg Q4 hours, codeine prn Postop: BCL, homatropine 5.0%, fluorometholone 0.1% Q2 hours, tobramycin 0.3% QID, mepergan fortis Q4 to 6 hours prn

Quality Score

Adverse Effects

PZ.004 for overall discomfort, N/A but NS for peak discomfort or use of escape medication

1 infiltrate in diclofenac group and 1 infiltrate in placebo group; 1 delayed epithelial healing in diclofenac group

VAS (0 to 130 mm); CS (none, P!.05 mild, moderate, severe); Descriptors; use of escape medication

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 Efficacy

3

5

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

Table 3. (Cont.) Pain Measure-ments


Efficacy

Adverse Effects

Quality Score

Preop: tetracaine 0.5% Postop: chloramphenicol 0.5% QID 1 week, betamethasone 0.1% QID 2 weeks, fluorometholone 0.1% TID 3 months, acetaminophen-codeine 300/10 mg Q4 hr prn

VAS 0-10; use of escape medication

P!.05 for gabapentin vs placebo and for pregabalin vs placebo; NS for gabapentin vs pregabalin

Nausea (gabapentin)

5

Postop: BCL, moxifloxacin 0.5% QID, fluorometholone 0.1% QID, keterolac 0.4% up to QID, oxycodoneacetaminophen 5 mg/325 mg Q4-6 hr prn; NSAID PO prn; vitamin C 1 g PO QD 3 mo

VAS 0-10; use of escape medication

NS on VAS; PZ.048 for use of escape medication on POD1

Nausea

5

Postop: BCL, tetracaine, dexamethasone Q5 hrs, moxifloxacin Q5 hrs; Vitamin C 1 gm PO QD 1 year

VAS 0-10

P!.05

None

5


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Table 4. Efficacy and safety of pain relief medications versus placebo after PRK.

Analgesic Class Topical anesthetics

Topical NSAIDs

Oral GABA analogues

Topical opiates

Studies of Medication Versus Placebo* Proparacaine 0.05% Shahinian18 Tetracaine 1% Verma20 Diclofenac 0.1% Razmju21 Mohammadpour22 Assouline33 Tutton35 Sher37 Ketarolac 0.5% Razmju21 Rajpal31 Ketarolac 0.4% Solomon29 Nepafenac 0.1% Caldwell24 Indomethacin 0.1% Assouline33 Gabapentin Pakravan38 Kuhnle39 Lichtinger40 Pregabalin Pakravan38 Morphine 0.5% Faktorovich41

Efficacy (Pain Measurement Scale)

Adverse Effects

P!.001 to 0.002 (NRS)

Delayed epithelialization, NS

P!.0001 (VAS)

Delayed epithelialization, P!.0001

P!.05 (VAS) PZ.018 (NRS) PZ.05 (VAS) PZ.012 (VAS, CS) P!.05 (VAS, CS)

None None Delayed epithelialization, PZ.04 Delayed epithelialization, P!.05 Delayed epithelialization, PZ.014

P!.05 (VAS) PZ.001 (NRS)

None Delayed epithelialization, PZ.001

P!.001(NRS)

Delayed epithelialization, NS

P!.0001 to P!.0005 (VAS)

Delayed epithelialization, PZ.0014

PZ.05 (VAS)

None

P!.05 (VAS) NS (VAS), PZ.048 (escape medications) P!.05 (VAS)

Nausea Nausea None

P!.05 (VAS)

None

P!.05 (VAS)

None

CS Z categorical scale; GABA Z gamma-aminobutyric acid; NRS Z numerical rating scale; NS Z not statistically significant (P!.05 considered statistically significant pain relief); NSAID Z nonsteroidal anti-inflammatory drug; PRK Z photorefractive keratectomy; VAS Z visual analog scale All studies were double-masked. *First author

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 Safety 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. Topical Opiates 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).

Efficacy



Safety 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 DISCUSSION 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

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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


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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. REFERENCES 1. Wilson SE. Clinical practice.use of lasers for vision correction of nearsightedness and farsightedness. N Engl J Med 2004; 351:470–475 2. Stanley PF, Tanzer DJ, Schallhorn SC. Laser refractive surgery in the United States Navy. Curr Opin Ophthalmol 2008; 19:321–324 3. Trattler WB, Barnes SD. Current trends in advanced surface ablation. Curr Opin Ophthalmol 2008; 19:330–334 4. Shortt AJ, Allan BDS, Evans JR. Laser-assisted in-situ keratomileusis (LASIK) versus photorefractive keratectomy (PRK) for myopia. Cochrane Database Syst Rev 2013; 1:CD005135. Summary available at: http://onlinelibrary.wiley. com/doi/10.1002/14651858.CD005135.pub3/pdf/abstract. Accessed February 28, 2014 5. Skevas C, Katz T, Wagenfeld L, Richard G, Linke S. Subjective pain, visual recovery and visual quality after LASIK, EpiLASIK (flap off) and APRK d a consecutive, non-randomized study. Graefes Arch Clin Exp Ophthalmol 2013; 251:1175–1183 6. Belmonte C, Tervo TT. Pain in and around the eye. In: McMahon SB, Koltzenburg M, eds, Wall and Melzack’s Textbook of Pain. Philadelphia, PA, Elsevier/Churchill Livingstone, 2006; 887–901 7. Cherry PMH, Tutton MK, Adhikary H, Banerje D, Garston B, Hayward JM, Ramsell T, Tolia J, Chipman ML, Bell A, Neave CH, Fichte C. The treatment of pain following photorefractive keratectomy. J Refract Corneal Surg 1994; 10:S222–S225 8. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009; 139:267–284. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852 643/pdf/nihms155644.pdf. Accessed February 28, 2014 9. Cherry PMH. The treatment of pain following excimer laser photorefractive keratectomy: additive effect of local anesthetic drops, topical diclofenac, and bandage soft contact. Ophthalmic Surg Lasers 1996; 27:S477–S480 sio R Jr, Hutcheon AEK, 10. Netto MV, Mohan RR, Ambro Zieske JD, Wilson SE. Wound healing in the cornea: a review of refractive surgery complications and new prospects for therapy. Cornea 2005; 24:509–522

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First author: Ella G. Faktorovich, MD Refractive and Corneal Surgery, Pacific Vision Institute, San Francisco, California 94109, USA

Efficacy and safety of transdermal fentanyl in the control of postoperative pain after photorefractive keratectomy.

Pregabalin versus placebo in postoperative pain relief of patients' status post photorefractive keratectomy: a double-masked, randomized, prospective study.

Corneal Regeneration After Photorefractive Keratectomy: A Review.

Visual function after photorefractive keratectomy.

Prospective, randomized, contralateral eye comparison of tetracaine and proparacaine for pain control in laser in situ keratomileusis and photorefractive keratectomy.

Photorefractive keratectomy.

Repeated excimer laser treatment after photorefractive keratectomy.

Safety and Efficacy of Epi-Bowman Keratectomy in Photorefractive Keratectomy and Corneal Collagen Cross-Linking: A Pilot Study.

Wavefront-guided versus non-wavefront-guided photorefractive keratectomy for myopia: meta-analysis of randomized controlled trials.

Corneal Biomechanical Changes After Myopic Photorefractive Keratectomy.

Twenty-year follow-up of a randomized prospective clinical trial of excimer laser photorefractive keratectomy.

The effect of topical corticosteroids on refractive outcome and corneal haze after photorefractive keratectomy. A prospective, randomized, double-blind trial.

Stereoacuity after photorefractive keratectomy in myopia.

Paraformaldehyde-induced keratitis after photorefractive keratectomy.

Post-photorefractive Keratectomy Pain and Corneal Sub-basal Nerve Density.

Comparison of analgesic effect of preoperative topical diclofenac and ketorolac on postoperative pain after photorefractive keratectomy.

Comparison of 3 silicone hydrogel bandage soft contact lenses for pain control after photorefractive keratectomy.

Effect of topical diclofenac on postoperative photorefractive keratectomy pain: a randomized, controlled trial.

Comparison of the effect of cycloplegic versus NSAID eye drops on pain after photorefractive keratectomy.

Photorefractive Keratectomy in Keratoconus.

Efficacy and Safety of Different Aceclofenac Treatments for Chronic Lower Back Pain: Prospective, Randomized, Single Center, Open-Label Clinical Trials.

Application of cold patch in relieving pain after transepithelial photorefractive keratectomy.

Effect of Homatropine eye drops on pain after photorefractive keratectomy: A pilot study.

Wound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys.