The effects of the PASQUALE ARAGONA, GIULIANA TRIPODI, ROSARIA SPINELLA, topical administration EMILIA LAGANA, GIUSEPPE FERRERI of non-steroidal anti­ inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects Abstract demonstrated for the other NSAIDs when compared either with the placebo-treated eyes Purpose To study the changes in the corneal or with the fellow eyes. epithelium and corneal sensitivity of healthy Conclusions Despite a similar mechanism of subjects after the topical administration of action and analgesic activity to the other non-steroidal anti-inflammatory drugs NSAIDs tested, diclofenac was able to induce (NSAIDs; diclofenac, indomethacin, a reduction in corneal sensitivity. More flurbiprofen and ketorolad frequently used in studies are needed to determine the ocular therapy_ mechanism of action responsible for this Methods A double-masked parallel clinical effect. study was undertaken on 90 subjects (45 men, 45 women; Caucasian; age 21--46 years, mean ::':: Key words Corneal sensitivity, Diclofenac, SD 27.1 ::':: 5 years). The subjects were divided Flurbiprofen, Indomethacin, Ketorolac, Non­ into six groups: group 1 was treated with steroidal anti-inflammatory drugs placebo, group 2 with 0.1% diclofenac, group 3 with 0.1% indomethacin, group 4 with 0.03% Non-steroidal anti-inflammatory drugs flurbiprofen, group 5 with 0.5% ketorolac and (NSAlDs) act in reducing fever and alleviating group 6 with 0.4% oxybuprocaine. One eye pain that accompanies injury or inflammation. was randomly treated with the study drug and They inhibit cyclooxygenase, an enzyme the fellow eye was treated with placebo. The important for the synthesis of prostaglandins medications were instilled four times, at 5 min and certain related autacoids. The intervals. Assessment of the corneal prostaglandins, produced following injury by epithelium was carried out by vital fluorescein activation of the arachidonic acid cascade, stain before instillation and 5, 15, 30 and 60 min after instillation of the last drop. induce a state of hyperalgesia by lowering the Subjective burning sensation was assessed by threshold of activation of the pain afferent asking participants to rate burning on a scale nerves. NSAIDs act locally or near the point of P Aragona injury reducing the prostaglandin-induced G. Tripodi from 0 (none) to 3 (severe). After 1 week, R. Spinella assessment of corneal sensitivity was carried hyperalgesia.1 E. Lagana out by the Cochet-Bonnet method, repeating The topical ocular use of NSAlDs includes Ferreri G. the above scheme of instillation and maintenance of pupillary dilatation during Institute of Ophthalmology measurement times. surgery, and control of post-operative ocular University of Messina inflammation and pain, for example following Messina, Italy Results None of the study drugs, with the radial keratotomy? or photorefractive exception of oxybuprocaine, produced evident Dr Pasquale Aragona [:;!'J keratectomy.3 They are also used for the epithelial damage. All the drugs caused a Institute of Ophthalmology prevention and treatment of post-operative University of Messina mean burning sensation greater than the cystoid macular oedema 1 and for non-surgically viale Boccetta, 70 placebo. The diclofenac-treated group showed 1-98122 Messina, Italy a statistically significant decrease in corneal induced inflammatory disorders of the eye, Tel: +39 90343184 sensitivity (p < 0.001) at the measurement such as allergic conjunctivitis. A number of Fax: +39 902924819 carried out 15 min after instillation of the last different conditions, either physiological such e-mail: [email protected] drop and lasting up to the end of the study, as ageing, menstrual cycle or pathological like when the corneal anaesthesia was similar to trauma, glaucoma, hypoxia and corneal acidosis Received: 31 March 1999 Accepted in revised form: that induced by the topical anaesthetic after contact lenses wear, herpes simplex 15 September 1999 treatment. No significant changes were keratitis, diabetes, leprosy and trigeminal 206 Eye (2000) 14, 206--210 © 2000 Royal College of Ophthalmologists neuralgia,4-8 can affect corneal sensitivity. A decreased The eye drops were instilled in one eye 4 times at 5 corneal sensitivity was also described after ocular min intervals and the ocular surface studied by surgical procedures such as epikeratophakia,9 radial fluorescein stainl8 before drug instillation and 5,15, 30 keratotomylO and photo refractive keratectomy, II and and 60 min after the last drop was instilled. The fellow topical treatment with NSAIOsY-I5 eye was treated according to the same procedure, with Diclofenac sodium is a phenylacetic acid derivative the drop used in the placebo group. A subjective used, in clinical practice, for its analgesic properties. evaluation of the burning sensation was performed by Indomethacin, a methylated indole derivative, exerts its asking participants to rate burning, after each instillation, action through a prominent anti-inflammatory activity. on a scale ranging from 0 (none) to 3 (severe). Indomethacin also has an analgesic effect distinct from After 1 week the drugs were instilled again, following its anti-inflammatory properties with both a central and the same procedure previously described; the corneal peripheral action. Flurbiprofen is a propionic acid sensitivity measurements were performed before the derivative with a prevalent analgesic effect.16 Ketorolac instillation and 5, 15, 30 and 60 min after instillation of tromethamine is a member of the phenylalkanoic group the last drop, using the Cochet-Bonnet aesthesiometer of NSAIDs, which has shown marked analgesic (Luneau Ophtalmologie, Chartres, France). The properties.I7 The aim of the study was to compare the instrument consists of a 0.12 mm diameter nylon filament of variable length (from 0 to 60 mm) which is applied on effect of indomethacin, diclofenac, flurbiprofen and the cornea with a strength variable from 11 to 200 mg/ ketorolac on the corneal epithelium and on corneal 0.0113 mm2 (mg/S).19 The subjects were pOSitioned at the sensitivity of healthy volunteers. slit-lamp fixating on a distant point with the slit-lamp light positioned at about 60°, with low-intensity illumination. The measurements were started with the Material and methods filament at its maximal length (lowest pressure), which is 60 mm. The filament was advanced perpendicularly and Ninety subjects (45 men, 45 women; Caucasian; age the cornea touched gently. Measurements were taken at 21-46 years, mean ::':: SO 27.1 ::':: 5years) were enrolled in the central cornea and in the four peripheral quadrants. the study. Commercially available drugs were used. Six A positive response was registered when the subject groups each of 15 healthy volunteers, age and sex declared verbally the sensation of corneal touch. The matched, were studied. simple reflex blinking of the tested eye was not recorded Group 1, the control group, was treated with placebo as a positive response. If a positive response was not with the following solution: boric acid 99.75 mg, borax achieved the filament length was reduced by 5 mm and 7.45 mg, methyl-p-hydroxybenzoate 2.5 mg, polyethylene the procedure repeated. The filament length that glycol 400 1242.50 mg, disodium edetate 2.5 mg, purified determined the corneal sensation was registered and water quantum sufficit to 5 ml (mean age ::':: SO 28.7 ::':: 6.9 converted into milligrams/surface unit (mg/S) years; 8 women, 7 men). according to a table supplied by the instrument Group 2 was treated with 0.1 % diclofenac (Voltaren manufacturer. Ofta, Ciba Vision Ophthalmics, Hettlingen, Switzerland) The study was performed with a double-masked (26.2 ± 4 years; 7 women, 8 men). design since both the subjects and the examiner were Group 3 was treated with 0.1% indomethacin solution masked as to which eye received the drug. (Indocollirio, SIFI, Catania, Italy) (26.7 ::':: 3.6 years; 8 For statistical analysis of the results of corneal women, 7 men). epithelial damage Fisher's exact test was used; the results Group 4 was treated with 0.03% flurbiprofen (Ocufen, of corneal sensitivity (in mg/S) were carried out Allergan Pharmaceuticals, Westport, Co. Mayo, Ireland) conSidering for each eye the mean value obtained from (26.2 ± 3.3 years; 7 women, 8 men). the measurements of the five areas considered. Analysis Group 5 was treated with 0.5% ketorolac was performed using an analysis of variance. Results tromethamine (Acular, Allergan Pharmaceuticals, were expressed as the mean ::':: SO. A P value of � 0.05 Westport, Co. Mayo, Ireland) (24.9 ± 4 years; 8 women, was considered statistically significant. 7 men). Group 6 was treated with a topical anaesthetic solution Results of 0.4% oxybuprocaine chloridrate (Novesina, Novartis Farma, Orrigio (VA), Italy) (30 ::':: 6.1 years; 7 women, 8 No signs of corneal epithelial damage were found in the men). patients of the five groups treated with placebo or with Informed consent was obtained from all subjects. NSAIOs at any time of the study. Four subjects treated Exclusion criteria were: age over 50 years, contact lens with the topical anaesthetic showed mild corneal wear, and patients with present ocular diseases or with a epithelial defects (score 1 according to Lempl8) already history of diseases such as herpetic diseases or with present at 5 min after instillation of the last drop and previous ocular surgery. Also excluded were patients lasting up to the observation at 60 min (p = 0.04). who had taken topical or general treatment during the All groups instilled with NSAIDs complained of a previous month or with systemic diseases such as mild burning sensation lasting a few seconds after each diabetes. instillation. The grading of the subjective burning 207 3 200 T T 1# 170 2.5 " " ,t " 20 I - 2 t:' 18 !!! - - - ! 16 8 1.5 f-- f-- til � 14 - - - f-- r--- E 12 10 T - - - r---- I- 0.5 ' Before 5' 15' 30 60' Time a � / C Placebo 61Dlcloten.c atIndomethacm 0 Flurblprofen Ketorolac0 CAn.esthetic Fig. 2. Mean decrease in corneal sensitivity in the diclofenac-treated 2 group, expressed as an increase in weightlsurface unit (0.0113 mm ) Fig.