|Year : 2018 | Volume
| Issue : 4 | Page : 221-227
The effect of topical 1% nalbuphine versus 0.1% nepafenac on corneal epithelial wound healing and pain after photorefractive keratectomy
Basem M Ibrahim1, Mohamed S Ahmad2
1 Department of Ophthalmology, Zagazig University, Zagazig, Egypt
2 Department of Anesthesia and Intensive Care, Zagazig University, Zagazig, Egypt
|Date of Submission||14-Apr-2018|
|Date of Acceptance||27-Jun-2018|
|Date of Web Publication||20-Dec-2018|
Basem M Ibrahim
Department of Ophthalmology, Faculty of Medicine, Zagazig University, Zagazig 44519
Source of Support: None, Conflict of Interest: None
Purpose To compare nalbuphine 1% (opioid analgesic) eye drops and nepafenac 0.1% (NSAID) eye drops in terms of their effects on corneal re-epithelialization and pain after photorefractive keratectomy (PRK).
Design A randomized prospective double-masked contralateral eye study was conducted.
Patients and methods Thirty adult healthy patients who were undergoing bilateral PRK received nepafenac 0.1% eye drops in one eye and nalbuphine 1% eye drops in the contralateral eye, every 2 h on the day of surgery and then four times daily on postoperative days 1 through 5 after bandage contact lens insertion.
Patients were asked to fill out pain assessment questionnaires every 2 h (general pain and after-drop pain) starting right away after surgery and continuing through postoperative day 5. Postoperative follow-up visits were daily until the epithelial defect completely healed in both eyes. The patients were then examined weekly for 4 weeks. At each visit, the patients provided rating of the general pain and the after-drop pain, and the epithelial defect size was assessed until complete healing of the corneal epithelium.
Results The general pain scores were less and the after-drop pain scores were more in the nalbuphine group when compared with the nepafenac group, but with no statistically significant difference between them (P>0.05). The mean epithelial defect size was similar between nepafenac 0.1% and nalbuphine 1% eye drops at the procedure day, but there were statistically significant differences between them with more fast healing in the nalbuphine group from the first postoperative day until complete epithelial defect healing (P<0.05).
Conclusion Nalbuphine 1% eye drops may provide a new choice in controlling pain after PRK surgery with comparable efficacy and better epithelial healing when compared with nepafenac 0.1% eye drops.
Keywords: epithelial healing and photorefractive keratectomy, nalbuphine, nepafenac, pain
|How to cite this article:|
Ibrahim BM, Ahmad MS. The effect of topical 1% nalbuphine versus 0.1% nepafenac on corneal epithelial wound healing and pain after photorefractive keratectomy. Delta J Ophthalmol 2018;19:221-7
|How to cite this URL:|
Ibrahim BM, Ahmad MS. The effect of topical 1% nalbuphine versus 0.1% nepafenac on corneal epithelial wound healing and pain after photorefractive keratectomy. Delta J Ophthalmol [serial online] 2018 [cited 2019 Mar 23];19:221-7. Available from: http://www.djo.eg.net/text.asp?2018/19/4/221/248082
| Introduction|| |
Laser in-situ keratomileusis is undoubtedly the most common refractive surgery procedure nowadays, yet certain limitations such as thin corneas, large pupils, corneal surface irregularities and epithelial basement membrane diseases with superficial opacities have made way for the development of photorefractive keratectomy (PRK) .
Despite the increase in selection of PRK as a refractive procedure, it does have certain drawbacks. One of the main concerns of patients, after PRK, is the severe pain, which usually starts on the first day postoperatively and continues until complete re-epithelialization occurs ,.
The human cornea is one of the most richly innervated sites in the human body. Noci-receptors respond to pain stimuli and carry signals via sensory afferent nerve fibers to the brain .
Systemic analgesics are routinely used in an attempt to control postoperative pain but were associated with adverse effects such as nausea, gastritis, and sedation. Topical NSAIDs have been the most favorable option in pain reduction after PRK. Variability in efficacy between different NSAIDs has been reported in numerous studies and is attributed mainly to difference in pharmaceutical properties . Nepafenac 0.1% has been the most commonly used NSAID in pain control after PRK . The pro-drug nepafenac is absorbed by the cornea and is then converted to amfenac, which is a potent inhibitor of cyclooxygenase-1 and cyclooxygenase-2 . However, NSAIDs may delay corneal wound healing owing to epithelial toxicity and the enhancement of lytic enzymes .
Various trials have suggested that topically applied opioids may provide analgesia through peripheral receptors via the neuro-immune pathway . Nalbuphine is able to achieve mild to moderate analgesia owing to its action as a κ agonist, μ antagonist opioid .
Lee et al. , evaluated the effect of topical application of 0.8% nalbuphine on postoperative ocular pain in dogs after phacoemulsification, and they recorded that there were significant decreases in corneal touch threshold, blepharospasm, and eye blink frequency after the topical nalbuphine treatment. This indicated that topical application of 0.8% nalbuphine solution can produce a rapid reduction of corneal discomfort .
The aim of this study was to compare nalbuphine 1% eye drops and nepafenac 0.1% eye drops in terms of their effects on corneal re-epithelialization and pain after PRK.
| Patients and methods|| |
This study was carried out between June 2017 and January 2018 at Al-Fat’h Eye Hospital, Zagazig City, Sharkia Governorate, Egypt.
The study was approved by the Local Ethical Committee of Al-Fat’h Eye Hospital.
A written consent was obtained from the patients before participating in the study which included an explanation of the study as well as the possible adverse effects of medications and the complications of the procedure.
This was a randomized prospective double-masked contralateral eye study to compare the effects of topical application of nepafenac 0.1% (NSAID) eye drops and nalbuphine 1% (opioid analgesic) eye drops in terms of their effects on corneal re-epithelialization and pain after PRK.
A random assignment list was designed by a technician who specified the masked study medication to each eye. Surgeon, patients, and postoperative examiner remained masked at all times and follow-up visits.
The study included 30 patients above 18 years old with healthy ocular condition for whom PRK surgery was performed. All patients were myopic and had an average error (spherical equivalent) of −4.0 D in each eye, a best-corrected visual acuity of 20/30 or better in each eye, and a stable refraction for at least 1 year.
Patients with history of any surgery in either eye, known history of any situation that could delay wound healing or allergy to any component of the study medications, PRK in only one eye, patients on systemic NSAIDs medication for any other diseases, concurrent use of glaucoma or allergy eye drops, dry eyes, pregnancy, and breast-feeding patients were excluded from the study.
All patients underwent a complete eye examination including slit-lamp examination, best-corrected visual acuity, cycloplegic refraction, and Pentacam topography (Oculus Pentacam HR, Wetzlar, Germany). Contact lenses were prohibited 1 week before surgery.
All patients were administered three drops of Benoxinate HCL 0.4% eye drops (Benox eye drops; EIPICO Pharmaceuticals, Cairo, Egypt) 5 min apart in both eyes before surgery. Epithelial debridement was performed manually with a spatula with consistent size between 9.5 and 10 mm in all eyes. No alcohol debridement of the epithelium was allowed during the procedure, and mitomycin C was not used at the end of the surgery. The stromal bed was irrigated with balanced salt solution (Ophtha Surgical Inc., Ahmedabad, Gujarat, India) and was dried with a Weck-Cel microsponge (Medtronic Inc., Minneapolis, Minnesota, USA). The ablation zone was 9.0 mm or less and was equal in both eyes. WaveLight EX500 laser (Alcon Laboratories Inc., Orlando, Florida, USA) was used for both conventional and wavefront-guided ablations. A bandage contact lens was applied to each eye after the application of topical moxifloxacin 0.5% and prednisolone acetate 1% eye drops. Patients underwent PRK surgery in both eyes on the same day.
Postoperative treatment consisted of gatifloxacin 0.3% eye drops four times daily for 7 days, prednisolone acetate 1% eye drops four times daily for 7 days that was tapered gradually over 14 days, and lubricant eye drops for 21 days. Every eye used separate, although the same medications to decrease the risk of cross-infection if occurs. Nepafenac 0.1% eye drops (Nevanac 0.1%; Alcon Laboratories Inc.) and nalbuphine 1% drops were topically applied, one specified to each eye in a random and masked way, every 2 h following PRK on the day of surgery and then four times daily on postoperative days 1 through 5. Nalbuphine 1% drops were prepared by dilution of nalbuphine HCl 20 mg per 1 ml ampoule (Amoun Pharmaceutical Company, Cairo, Egypt) with an equal amount of lubricant eye drops [Polyfresh eye drops (sodium hyaluronate 0.2%); Orchidia Pharmaceutical Industries, El Obour City, Egypt]. No drug interaction had been reported between nalbuphine HCl and sodium hyaluronate. Each dropper was marked with labels with a large ‘R’ or ‘L’ letters that corresponded to the right or left eye, respectively. Patients were instructed to wear sunglasses with ultraviolet ray protection for 1 week.
Postoperative follow-up visits were daily until epithelial defects completely healed in both eyes. The patients were then examined weekly for 4 weeks. The epithelial defect size was measured with a slit-lamp micrometer with the aid of fluorescein staining, if needed. Horizontal and vertical diameters of the defect were recorded at each visit. Once the epithelial defect had healed the contact lens was removed. Visual acuity and refraction were performed starting 1 week postoperatively.
Patients were asked to fill out pain assessment questionnaires every 2 h, starting right away after surgery and continuing through postoperative day 5. Patients were instructed on how to assess their pain levels for each eye using a well-documented method of pain assessment named the visual analog scale that ranged from 1 to 10, where 1 means ‘no pain at all’ and 10 means ‘unbearable pain’ . Study medications were then installed in both eyes, and the patients were asked to grade the pain immediately after installation of drops (after-drop pain). The same pain scale was used for the after-drop pain. The questionnaires were collected daily from patients at follow-up visits until epithelial defects completely healed in both eyes.
The collected data were computerized and statistically analyzed using statistical package for social science program (version 18.0; SPSS Inc., Chicago, Illinois, USA). Qualitative data were represented as frequencies and relative percentages. Quantitative data were expressed as mean±SD and range. Independent t test was used to calculate the difference between quantitative variables in the two groups in normally distributed data, and Mann–Whitney test was used in abnormally distributed data. Two-way analysis of variance test was used to calculate the difference between quantitative variables in each group at different times in normally distributed data, and Friedman test was used in abnormally distributed data and qualitative data. The significance level for all aforementioned statistical tests were done. The threshold of significance was fixed at 5% level (P value), where P value of more than 0.05 indicated nonsignificant results, P value of less than 0.05 indicated significant results, and P value of less than 0.01 indicated highly significant results.
| Results|| |
This study included 30 patients (60 eyes), including 17 (56.7%) men and 13 (43.3%) women, for whom bilateral PRK was performed. The mean age of the patients was 29±5.89 years (range, 19–42 years).
All patients completed the study except for one patient who was uncooperative and withdrew from the study.
Regarding the postoperative average pain scores, there were no statistically significant differences between the two groups throughout the postoperative follow-up days, but there was a statistically highly significant (P<0.01) improvement in pain sensation throughout the postoperative days in each group ([Table 1]).
|Table 1 Comparison of general pain score in the two groups at different times|
Click here to view
The general pain scores were lower in eyes of the topical nalbuphine group than in eyes of the topical nepafenac group, although the difference between the two groups was not statistically significant (P>0.05, [Table 1] and [Figure 1]).
There was a statistically significant difference (P<0.05) in the mean epithelial defect size between the two groups with smaller epithelial defects in eyes of the topical nalbuphine group than in eyes of the topical nepafenac group from the first postoperative day until complete epithelial healing with the exception of the procedure day where the mean epithelial defect size was comparable between the two groups ([Table 2]).
|Table 2 The mean epithelial defect size in the two groups at different times|
Click here to view
On the contrary, there was a statistically highly significant (P<0.01) decrease in the mean epithelial defect size throughout the postoperative days in both groups ([Table 2] and [Figure 2]).
|Figure 2 The mean epithelial defect size in the two groups at different times.|
Click here to view
There were no statistically significant differences in subjective comfort and pain sensation after instillation of eye drops between nepafenac 0.1% and nalbuphine 1% throughout all postoperative days ([Table 3]).
|Table 3 Comparison of after-drop pain in the two groups at different times|
Click here to view
The after-drop pain was nearly comparable on the procedure day and postoperative day 1. However, from the second postoperative day and on, lower scores were noted in the nepafenac group, yet the difference was still statistically insignificant ([Table 3] and [Figure 3]).
| Discussion|| |
PRK will stay as a vital procedure in refractive surgery and will persist to be a brilliant alternative for many patients. Some of the drawbacks that largely limit the wide use of PRK are the postoperative pain and discomfort, which occur because of epithelial debridement . With the progress of new methods of analgesia targeting specific receptors on the corneal nerves, refractive surgeons can overcome this drawback and achieve patient comfort with greater safety . The ideal analgesic should be effective in alleviating pain, without interfering with corneal epithelial healing and with no adverse effects and should be applied topically without systemic penetration and systemic adverse effects.
To our knowledge, this is the first study to compare the topical application of NSAID, nepafenac 0.1% eye drops, with a topical opioid analgesic, nalbuphine 1% eye drops, after PRK.
Nepafenac 0.1% has been the most commonly used NSAID in pain control after PRK. It offers greater comfort upon installation and appears to be well tolerated without significant adverse effects . On the contrary, Ella and Allan  used topical morphine (a natural opioid analgesic) eye drops to control pain after PRK surgery. They found that morphine can significantly reduce pain after PRK without inhibiting corneal re-epithelialization and without other adverse effects of topical NSAIDs such as keratitis, nonhealing epithelial defects, corneal melting, and perforation . Opioid receptors have been identified on the peripheral nerves of inflamed or injured tissue . This opens the gate for research on analgesic efficacy of locally applied exogenous opioids using small doses that have no systemic effects. Most published data depend on studies of intra-articular use of morphine after knee surgery ,.
Nalbuphine is a synthetic opioid analgesic that can be applied topically in the eye and provides analgesia through peripheral receptors via the neuro-immune pathway . In a meta-analysis of randomized controlled trials done by Zeng et al.  to compare nalbuphine with morphine for their analgesic effects and safety, they concluded that the analgesic efficacy of nalbuphine is comparable to morphine, but nalbuphine provides a better safety profile than morphine in the aspect of certain adverse effects, especially related to pruritus, nausea, vomiting, and respiratory depression. According to the Egyptian drug authority of the Ministry of Health, nalbuphine has less degree of restriction than morphine.
In the present study, the average pain scores using pain assessment questionnaires that were recorded by the patients showed less pain in eyes of the topical nalbuphine group than in eyes of the topical nepafenac group, although the difference was not statistically significant. Ella and Allan  reported that PRK patients in the topical morphine group experienced up to 50% less pain on average compared with the patients in the control group. Similarly, Lee et al.  found that topical application of 0.8% nalbuphine solution can produce a rapid reduction of corneal discomfort in dogs after phacoemulsification. Conversely the effect of topical 1% nalbuphine on corneal sensitivity and epithelization after experimental lamellar keratectomy in rabbits was assessed by Silva et al. . They reported that it has no effect on corneal analgesia and does not accelerate corneal epithelialization rate in rabbits after experimental lamellar keratectomy .
In the present study, the mean epithelial defect size was comparable between the two groups on the procedure day only but was smaller in eyes of the topical nalbuphine group than in eyes of the topical nepafenac group from the first postoperative day until complete epithelial healing, and the difference was statistically significant.
After reviewing the efficacy and safety of pain relief medications after PRK, Faktorovich and Melwani  concluded that although tetracaine 1% and nepafenac 0.1% tended to have the most analgesic effect, delayed corneal re-epithelialization was found to be a common adverse effect of both topical anesthetics and topical NSAIDs.
Besides the general pain estimation, patients recorded the subjective sensations of pain that occur after topical application of the study drops (after-drop pain). There were almost no differences between nepafenac 0.1% and nalbuphine 1% in subjective comfort and pain sensation after instillation of eye drops on the procedure day and postoperative day 1. This was most probably attributed to the masking effect of the severe general pain, which was present in the first 2 days. However, from the second postoperative day and on, the difference became more pronounced with lower scores noted in the nepafenac group, although it was statistically insignificant. This is most probably owing to the acidic nature of the nalbuphine solution (adjusted pH, 3.5–3.7) .
Donnenfeld et al.  conducted a double-masked study to compare the effects of ketorolac 0.4% and nepafenac 0.1% on epithelial healing and pain after PRK and found that nepafenac 0.1% drops had better comfort after instillation in PRK patients.
| Conclusion|| |
Nalbuphine 1% eye drops (opioid analgesic) may provide a new choice in controlling pain after PRK surgery with comparable efficacy and better epithelial healing when compared with nepafenac 0.1% (NSAID) eye drops.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ambrosio JR, Wilson S. LASIK vs LASEK vs PRK: advantages and indications. Semin Ophthalmol 2003; 18:2–10.
Assouline M, Renard G, Arne JL, David T, Lasmolles C, Malecaze F, Pouliquen YJ. A prospective randomized trial of topical soluble 0.1% indomethacin versus 0.1% diclofenac versus placebo for the control of pain following excimer laser photorefractive keratectomy. Ophthalmic Surg Lasers 1998; 29:365–374.
McCarty CA, Garrett SK, Aldred GF, Taylor HR. Assessment of subjective pain following photorefractive keratectomy. J Refract Surg 1996; 12:365–369.
Silva ML, Piso DY, Ribeiro AP, Laus JL. Topical 1% Nalbuphine on corneal sensivity and epithelization after experimental lamellar keratectomy in rabbits. Cienc Rural Santa Maria 2012; 42:679–684.
Faktorovich EG, Melwani K. Efficacy and safety of pain relief medications after photorefractive keratectomy: review of prospective randomized trials. J Cataract Refract Surg 2014; 40:1716–1730.
Donnenfeld ED, Holland EJ, Durrie DS, Raizman MB. Double-masked study of the effects of Nepafenac 0.1% and Ketorolac 0.4% on corneal epithelial wound healing and pain after photorefractive keratectomy. Adv Therapy 2007; 24:852–862.
Gamache DA, Graff G, Brady MT, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation. I. Assessment of anti-inflammatory efficacy. Inflammation 2000; 24:357–370.
Reviglio VE, Rana TS, Li QJ, Ashraf MF, Daly MK, O’Brien TB. Effects of topical nonsteroidal anti-inflammatory drugs on the expression of matrix metalloproteinases in the cornea. J Cataract Refract Surg 2003; 29:989–997.
Stiles J, Honda CN, Krohne SG, Kazacos EA. Effects of the topical administration of 1% morphine sulfate solution on signs of pain and corneal would healing in dogs. Am J Vet Res 2003; 64:813–818.
Hoskin PJ, Hanks GW. Opioid agonist-antagonist drugs in acute and chronic pain states. Drugs 1991; 41:326–344.
Lee CH, Lin SL, Chi TT, Chang SH, Wang HC. Effect of topical administration of 0.8% nalbuphine on the cornea in dogs after phaco-emulsification. J Vet Med Sci 2013; 75:1041–1047.
Ella GF, Allan IB. Effect of topical 0.5% morphine on postoperative pain after photorefractive keratectomy. J Refract Surg 2010; 26:934–941.
Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 1995; 332:1685–1690.
Stein C, Comisel K, Haimerl E, Yassouridis A, Lehrberger K, Herz A, Peter K. Analgesic effect of intra-articular morphine after arthroscopic knee surgery. N Engl J Med 1991; 325:1123–1126.
Liu K, Wang JJ, Ho ST, Liaw WJ, Chia YY. Opioids in peripheral analgesia: intra-articular morphine for pain control after arthroscopic knee surgery. Acta Anaesthesiol Sing 1995; 33:217–221.
Zeng Z, Jianhua L, Chang S, Yuanli C, Tong G, Qing-ping W et al.
A comparison of nalbuphine with morphine for analgesic effects and safety: meta-analysis of randomized controlled trials. Sci Rep 2015; 5:10927.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]