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Topical non‐steroidal anti‐inflammatory drugs for analgesia in traumatic corneal abrasions

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Abstract

Background

Traumatic corneal abrasions are relatively common and there is a lack of consensus about analgesia in their management. It is therefore important to document the clinical efficacy and safety profile of topical ophthalmic non‐steroidal anti‐inflammatory drugs (NSAIDs) in the management of traumatic corneal abrasions.

Objectives

To identify and evaluate all randomised controlled trials (RCTs) comparing the use of topical NSAIDs with placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions (including corneal abrasions arising from foreign body removal), to reduce pain, and its effects on healing time.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 2), MEDLINE Ovid (1946 to 30 March 2017), Embase Ovid (1947 to 30 March 2017), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 30 March 2017), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/); searched 30 March 2017, ZETOC (1993 to 30 March 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 30 March 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 30 March 2017 and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 30 March 2017. We did not use any date or language restrictions in the electronic searches for trials.We checked the reference lists of identified trials to search for further potentially relevant studies.

Selection criteria

RCTs comparing topical NSAIDs to placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions.

Data collection and analysis

Two review authors independently performed data extraction and assessed risks of bias in the included studies. We rated the certainty of the evidence using GRADE.

Main results

We included nine studies that met the inclusion criteria, reporting data on 637 participants.The studies took place in the UK, USA, Israel, Italy, France and Portugal. These studies compared five types of topical NSAIDs (0.1% indomethacin, 0.03% flurbiprofen, 0.5% ketorolac, 1% indomethacin, 0.1% diclofenac) to control (consisting of standard care and in four studies used placebo eye drops). Overall, the studies were at an unclear or high risk of bias (particularly selection and reporting bias). None of the included studies reported the primary outcome measures of this review, namely participant‐reported pain intensity reduction of 30% or more or 50% or more at 24 hours. Four trials, that included data on 481 participants receiving NSAIDs or control (placebo/standard care), reported on the use of ‘rescue’ analgesia at 24 hours as a proxy measure of pain control. Topical NSAIDs were associated with a reduction in the need for oral analgesia compared with control (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.34 to 0.61; low‐certainty evidence). Approximately 4 out of 10 people in the control group used rescue analgesia at 24 hours. No data were available on the use of analgesia at 48 or 72 hours.

One trial (28 participants) reported on the proportion of abrasions healed after 24 and 48 hours. These outcomes were similar in both arms of the trial. (at 24 hours RR 1.00 (0.81 to 1.23); at 48 hours RR 1.00 (0.88 to 1.14); low‐certainty evidence). In the control group nine out of 10 abrasions were healed within 24 hours and all were healed by 48 hours. Complications of corneal abrasions were reported in 6 studies (609 participants) and were infrequently reported (4 complications, 1 in NSAID groups (recurrent corneal erosion) and 3 in control groups (2 recurrent corneal erosions and 1 corneal abscess), very low‐certainty evidence). Possible drug‐related adverse events (AEs) were reported in two trials (163 participants), with the number of adverse events low (4 AEs, 3 in NSAID group, including discomfort/photophobia on instillation, conjunctival hyperaemia and urticaria, and 1 in the control group, corneal abscess) very low‐certainty evidence.

Authors' conclusions

The findings of the included studies do not provide strong evidence to support the use of topical NSAIDs in traumatic corneal abrasions. This is important, since NSAIDs are associated with a higher cost compared to oral analgesics. None of the trials addressed our primary outcome measure of participant‐reported pain intensity reduction of 30% or more or 50% or more at 24 hours.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Topical non‐steroidal anti‐inflammatory drugs (NSAIDs) for the treatment of pain in traumatic corneal abrasions

What is the aim of this review?
The aim of this Cochrane Review was to find out if topical (applied directly to the surface of the eye) non‐steroidal anti‐inflammatory drugs (NSAIDs) for traumatic corneal abrasions reduce pain. Cochrane researchers collected and analysed all relevant studies to answer this question. We found nine studies.

Key messages
It is unclear if using topical NSAIDs is helpful in traumatic corneal abrasions. Topical NSAIDs cost more to use than alternative treatments such as oral pain‐killing tablets.

What was studied in the review?
A corneal abrasion is a scratch on the cornea of the eye. The cornea is the clear window that is in front of the iris, which is the coloured part of the eye. The cornea is important both for vision and for protecting the eye. When a corneal abrasion occurs, it causes significant pain and discomfort. A traumatic corneal abrasion is a corneal abrasion caused by an injury, such as the eye being poked or something like dirt or sand being trapped under the eyelid and scratching the cornea.

NSAIDs are one form of pain management for people with corneal abrasions.They may reduce the pain.

What are the main results of the review?
The Cochrane researchers found nine relevant studies. Three studies each were from the UK and the USA, one from Italy, one from Israel and one from France/Portugal. These studies used five types of topical NSAIDs (0.1% indomethacin, 0.03% flurbiprofen, 0.5% ketorolac, 1% indomethacin, 0.1% diclofenac). The studies compared the topical NSAIDs with antibiotic eye drops, artificial tears, eye patching and dummy (placebo) eye drops. Three of the studies were funded by the manufacturer while the other six studies did not report their funding source.

The results of the review show that:
∙ It is unclear if people treated with topical NSAIDs experience a clinically meaningful reduction in pain compared with people being treated with placebo or standard care (antibiotic eye drops, artificial tears, eye patching) but they may use less oral pain killers.

∙ Where drug‐related side effects, and complications of corneal abrasion (e.g. poor healing or infection) were reported (in two trials), the numbers were low.

How up‐to‐date is this review?
Cochrane researchers searched for studies that had been published up to March 2017.

Authors' conclusions

Implications for practice

Traumatic corneal abrasions are a common presentation in both general emergency departments and specialist eye units. However, there remains a lack of high‐quality evidence to inform the management of this condition. Prophylactic antibiotics with or without cycloplegia are typically used, although based on the results of a previous Cochrane Review (Lim 2016) eye patching is no longer recommended. Most simple traumatic abrasions heal within one or two days, but during this period they can be associated with significant pain, foreign body sensation and photophobia. It has been suggested that topical NSAIDs may be used to provide effective analgesia, which could potentially reduce the requirement for oral analgesia, although there have been some concerns in the literature regarding possible impairment of corneal wound healing and drug‐induced adverse reactions.

The findings from the trials included in this review do not provide strong evidence to support the use of topical NSAIDs in traumatic corneal abrasions. This is important, since topical NSAIDs are associated with a higher cost compared to oral analgesics. None of the trials addressed our primary outcome measure of participant‐reported pain intensity reduction of 30% or more or 50% or more at 24 hours.

Although there was some evidence from four trials that the use of topical NSAIDs led to a reduced need for 'rescue' analgesia at 24 hours, this finding should be interpreted with caution, since the certainty of the evidence was low.

Implications for research

Investigators planning future trials on the effectiveness of topical NSAIDs for corneal abrasions should attempt to address the sources of bias identified in the studies included in this review; specifically the use of appropriate methods for randomisation and allocation concealment. Furthermore, strategies should be developed to improve collection of outcome data and reduce attrition bias. Although the use of unidimensional visual analogue scales (VASs) has been shown to be a valid and reproducible method in studies evaluating pain relief, investigators may be tempted to overestimate the clinical importance of small differences in VAS scores. Further work in this context should attempt to determine the minimum clinically important difference as measured by VAS pain scores that represents small, moderate, or large treatment effects.

Summary of findings

Open in table viewer
Summary of findings for the main comparison. Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions

Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions

Patient or population: analgesia in traumatic corneal abrasions
Setting: hospital emergency departments
Intervention: topical NSAIDs
Comparison: placebo/standard care

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with Placebo/usual care

Risk with Topical NSAIDs

Participant‐reported pain intensity reduction of 30%/50% or greater at 24 hours

See comment

See comment

N/A

N/A

N/A

None of the included studies reported the primary outcome measures for this review

Use of rescue oral analgesia at 24 hours

400 per 1,000

184 per 1,000
(136 to 244)

RR 0.46
(0.34 to 0.61)

481
(4 RCTs)

⊕⊕⊝⊝
LOW1

Use of rescue oral analgesia at 48/72 hours

See comment

See comment

N/A

N/A

N/A

None of the included studies reported rescue analgesia at 48 hours or at 72 hours as an outcome measure

Proportion of abrasions healed after 24 hours

900 per 1,000

900 per 1,000
(729 to 1,000)

RR 1.00
(0.81 to 1.23)

28
(1 RCT)

⊕⊕⊝⊝
LOW1

Proportion of abrasions healed after 48 hours

1,000 per 1,000

1000 per 1,000
(880 to 1,000)

RR 1.00
(0.88 to 1.14)

28
(1 RCT)

⊕⊕⊝⊝
LOW1

Complications of corneal abrasion

10 per 1,000

4 per 1,000
(1 to 29)

RR 0.44
(0.07 to 2.96)

609
(6 RCTs)

⊕⊝⊝⊝
VERY LOW1,2

Drug‐related adverse events

10 per 1,000

30 per 1,000
(3 to 276)

RR 2.95
(0.32 to 27.60)

163
(2 RCTs)

⊕⊝⊝⊝
VERY LOW1,2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Downgraded two levels for limitations in study design and implementation

2Downgraded one level for imprecision (wide confidence intervals that cross the null effect)

Background

Description of the condition

A corneal abrasion results from a disruption in the integrity of the corneal epithelium and generally results from physical external forces scraping the corneal surface (Wilson 2004). Traumatic corneal abrasions are very common ophthalmic injuries and represent a significant healthcare burden to general emergency departments (EDs), ophthalmology emergency departments and General Practitioners (Chiapella 1985; Edwards 1987; Fenton 2001; Shields 1991). In one study, ophthalmic emergencies accounted for 6.1% of all ED attendances at a district general hospital over a 12‐month period; 65% of these were trauma‐related, of which 24% were corneal abrasions (Edwards 1987). Traumatic corneal abrasions also represent a significant economic burden on society in general. For example, in the USA, corneal abrasions account for approximately 15% of all work‐related eye diseases that cause missed time from work (Harris 2008).

A traumatic corneal abrasion is also associated with significant patient morbidity. Its diagnosis is suggested by a history of recent ocular trauma (usually unilateral) and subsequent acute pain, tearing, photophobia, foreign body sensation, with or without effects on visual acuity (blurred vision). Other symptoms include: pain with extraocular muscle movement, blepharospasm and headache. Deeper scratches can cause corneal scarring that can impair vision to the point where corneal transplantation is needed. Recurrent corneal erosion may follow corneal trauma and can produce disabling ocular symptoms and predispose the cornea to infection (Watson 2013).

Description of the intervention

Although current treatment recommendations for traumatic corneal abrasions stress the use of topical antibiotics and topical (ophthalmic) or oral analgesics (Wilson 2004), there is no universal consensus regarding corneal abrasion management (Sabri 1998). Routine use of topical anaesthetics is not recommended, due to recognised corneal complications associated with their use (Pharmakakis 2002; Yagci 2011). Most corneal abrasions heal with the use of topical antibiotics (drops or ointment) and analgesics (topical (ophthalmic) or oral). Regarding management of the pain associated with corneal abrasions, topical ophthalmic non‐steroidal anti‐inflammatory drugs (NSAIDs) have demonstrable efficacy, particularly where potential opioid‐induced sedation is intolerable (Weaver 2003). However, there is also no consensus regarding management of the pain caused by traumatic corneal abrasions. A national survey of 470 members of the Canadian Association of Emergency Physicians revealed wide variation in pain management preferences for traumatic corneal abrasions; these included oral analgesics (82.1%), cycloplegics (65.1%) and topical NSAIDs (52.8%) (Calder 2004).  

There have been scattered reports of adverse effects, including corneal melting, associated with topical NSAIDs, particularly after cataract surgery, concurrent use of topical steroids and prolonged administration (Guidera 2001; Lin 2000). A previous systematic review of the use of the topical NSAIDs for corneal abrasions failed to perform a meta‐analysis of adverse effects due to insufficient data (Calder 2005).

How the intervention might work

Topical NSAID use results in a clinically significant decrease in pain (by an average of 1.3 cms on a standard 10‐cm pain scale), a decrease in oral analgesic use and a decrease in requirement for narcotic analgesia (Weaver 2003). Topical NSAID use has been shown to be associated with earlier return to work after a traumatic corneal abrasion (Kaiser 1997).

Why it is important to do this review

The use of topical NSAIDs for the management of pain in traumatic corneal abrasions is a clinically valid topic for a Cochrane Review for many reasons. Firstly, corneal abrasions are relatively common. Secondly, they are associated with significant morbidity, healthcare costs and societal economic burden. Thirdly, there is a lack of consensus regarding analgesia in traumatic corneal abrasions. Fourthly, as the use of topical ophthalmic NSAIDs is very common, it is important to document any incidence of adverse effects when used in the management of traumatic corneal abrasions. Furthermore, a Cochrane Review that is continuously updated as new evidence is published may lead to clinical practice guidelines which may improve the efficiency and quality of patient care (Edwards 1987; Fenton 2001; Thyagarajan 2006). Moreover, the last non‐Cochrane systematic review on this topic was published almost twelve years ago (Calder 2005). This Cochrane Review aims to synthesise the current best evidence, which will be continuously updated as relevant new trials are published, regarding the role of topical NSAIDs for analgesia in traumatic corneal abrasions (including corneal abrasions arising from foreign body removal).

Objectives

To identify and evaluate all randomised controlled trials (RCTs) comparing the use of topical NSAIDs with placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions (including corneal abrasions arising from foreign body removal) to reduce pain, and its effects on healing time.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs in all languages. A RCT was defined as a study in which participants were allocated to treatment groups on the basis of a method to generate a random sequence (for example, using random‐number tables).

We did not include studies with cross‐over designs because these are not appropriate designs for the clinical condition of interest in this review and for this research question.

Types of participants

We included adults aged 18 and over with traumatic corneal abrasion(s) (including corneal abrasions arising from foreign body removal).

Types of interventions

The target intervention was topical NSAIDs (dose as defined by study authors, either overall daily dose or number of drops per day) in adults with traumatic corneal abrasions (including corneal abrasions arising from foreign body removal), compared to the following interventions:

  1. Administration of cycloplegics (e.g. cyclopentolate drops, homatropine drops).

  2. Administration of oral analgesics (e.g. NSAIDs, opioids, paracetamol/acetaminophen).

  3. Administration of ocular lubricants (e.g. artificial tears (hydrogels)).

  4. Administration of topical antibiotics (e.g. chloramphenicol, fusidic acid, trimethoprim/polymyxin).

  5. Eye patching.

Types of outcome measures

Primary outcomes

  1. Participant‐reported pain intensity reduction of 30% or more at 24 hours (dichotomous data).

  2. Participant‐reported pain intensity reduction of 50% or more at 24 hours (dichotomous data).

Secondary outcomes

  1. Use of 'rescue' analgesia (i.e. oral analgesia) at 24 hours, 48 hours and 72 hours.

  2. Percentage/proportion healed after 24 and 48 hours (healing should have been ascertained using fluorescein staining or slit‐lamp examination).

  3. Complications of corneal abrasion (e.g. corneal ulceration, corneal infections, recurrent corneal erosion syndrome) as defined by the study authors.

  4. Whether the use of concurrent topical antibiotics (drops or ointments) with additional lubricating effects reduced pain.

Adverse effects (severe, minor)

We looked for the following adverse effects:

  1. Drug‐related adverse events (e.g. corneal melting, corneal scarring, allergic conjunctivitis or keratitis secondary to ocular medications).

  2. Other adverse events as defined by the study authors.

Search methods for identification of studies

Electronic searches

The Cochrane Eyes and Vision Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials. There were no language or publication year restrictions. The date of the search was 30 March 2017.

  • Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 30 March 2017) (Appendix 1);

  • MEDLINE Ovid (1946 to 30 March 2017) (Appendix 2);

  • Embase Ovid (1980 to 30 March 2017) (Appendix 3);

  • LILACS (Latin American and Caribbean Health Science Information database (1982 to 30 March 2017) (Appendix 4);

  • OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/; searched 30 March 2017) (Appendix 5);

  • ZETOC (1993 to 30 March 2017) (Appendix 6);

  • ISRCTN registry (www.isrctn.com/editAdvancedSearch; searched 30 March 2017) (Appendix 7);

  • US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 30 March 2017) (Appendix 8);

  • World Health Organization International Clinical Trials Registry Platform (www.who.int/ictrp; searched 30 March 2017) (Appendix 9).

Searching other resources

We made additional efforts to identify potential RCTs relevant to the topic from the references (and references of references) cited in primary sources. We did not impose any language restriction.

Data collection and analysis

Selection of studies

Two review authors (RM and OG) independently assessed the titles and abstracts of studies identified by relevance and design. We obtained full‐text versions of the articles if they appeared to meet the inclusion criteria in the initial assessment of studies. A third review author (AW) evaluated any discrepant judgements.

Data extraction and management

Two review authors (MB and MQ) independently extracted data using a standardised data collection form that included information on the name of the first author, year of publication, study design, study population and study setting. In addition to information pertaining to participant characteristics, study inclusion and exclusion criteria, details of the interventions compared and study outcomes, we extracted information on study methodology. This included the method of randomisation, allocation concealment, frequency and handling of withdrawals, and adherence to the intention‐to‐treat principle. We resolved disagreements through discussion and in consultation with a third review author (AW) as required.

Assessment of risk of bias in included studies

Two review authors (MB and MQ) independently assessed and rated the methodological quality of each trial using the Cochrane tool for assessing risk of bias as in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We judged the quality of the studies by evaluating them for the following domains:

  1. Random sequence generation.

  2. Allocation concealment.

  3. Masking of participants and personnel, and outcome assessment.

  4. Incomplete outcome data.

  5. Selective outcome reporting.

  6. Funding source.

  7. Other potential sources of bias.

We evaluated each study and assessed it separately for these domains. We judged each explicitly as follows:

  • Low risk of bias.

  • High risk of bias.

  • Unclear risk (lack of information or uncertainty over the potential for bias).

We entered the data on what was reported to have happened in the study in the 'Risk of bias' table in Review Manager 5 (Review Manager 5 2014). We present summary figures of the 'risk of bias in included studies' in the review. These provides a context for discussing the reliability of the results of this review. We resolved any disagreement by referring to a third review author (AW) to reach a consensus.

Measures of treatment effect

We calculated summary estimates of treatment effect with 95% confidence intervals (CIs) for each comparison. Our measure of treatment effect was the risk ratio (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes. Currently the review only includes analysis of dichotomous outcomes.

Unit of analysis issues

The unit of randomisation was the eye of individual trial participants. We did not anticipate that studies would have more than one eye affected in each individual; however, if this occurred we planned to note it in the review. If studies using a paired design were eligible for inclusion (i.e. studies assigning one eye to treatment and the fellow eye to control), we planned to use the generic inverse variance method to combine the results of such studies with those of studies randomising only one eye for each participant.

Dealing with missing data

No simple solution exists for the problem of missing data. We planned to handle this problem by contacting the investigators, whenever possible, to ensure that no data were missing for their study. We also planned to make explicit the assumptions of whatever method we used to cope with missing data.

Assessment of heterogeneity

We evaluated clinical heterogeneity (differences between studies in key characteristics of the participants, interventions or outcome measures). In the absence of clinical heterogeneity, we used the I2 statistic to describe the percentage of total variation across studies that is due to heterogeneity rather than chance (Higgins 2003). An I2 greater than 50% may represent substantial or considerable statistical heterogeneity (Higgins 2011). The importance we placed on the observed value of I2 depended on (i) magnitude and direction of effects, and (ii) strength of evidence for heterogeneity (P value from the Chi2 test and confidence interval for I2).

We also used visual inspection of the graphic representation of studies with their 95% CIs to assess heterogeneity. We generated tables and graphs using the analysis module included in RevMan (Review Manager 5 2014). We represent pooled risk ratios pictorially as a 'forest plots' to permit visual examination of the degree of heterogeneity between studies.

Assessment of reporting biases

We assessed reporting bias through careful attention to quality assessment, particularly methodology. We planned to use funnel plot analysis to assess publication bias if there were more than 10 studies included in the meta‐analysis. We also planned to use the Egger test (Egger 1997) to assess funnel plot asymmetry. A thorough search for unpublished studies through grey literature searches and contact with known experts in the field also helped to reduce the risk of publication bias.

Data synthesis

The results concentrate on the objectives and comparisons specified in the protocol for our review. We pooled data using a random‐effects model, because it was likely that the effects of topical NSAIDs may vary between studies. The random‐effects model takes into account between‐study variability as well as within‐study variability. When there were three or fewer trials, we used a fixed‐effect model. We performed meta‐analyses using RevMan 5 software (Review Manager 5 2014).

Subgroup analysis and investigation of heterogeneity

We planned to investigate heterogeneity by performing two subgroup analyses based on intuitive reasons. Firstly, we planned to perform subgroup analysis of different types of topical NSAIDs (for example, subgroup analysis of topical diclofenac and topical ketorolac). Secondly, we planned to perform subgroup analysis of traumatic corneal abrasions with different aetiologies, based on whether the abrasions are iatrogenic (arising from foreign body removal) or non‐iatrogenic in origin.

Sensitivity analysis

Finally, we planned to perform sensitivity analyses to test how sensitive the results were to reasonable changes in the assumptions that we made and in the methods for combining the data (Lau 1998). We planned to perform sensitivity analysis for randomised versus quasi‐randomised studies and eventually good‐quality studies versus poor‐quality studies.

Summary of findings

We used the principles of the GRADE system (Lau 1998) to assess the quality of the body of evidence associated with the primary outcome measure of this review (pain relief), and constructed a 'Summary of findings' (SoF) table using the GRADE software (GRADEpro 2014). The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality of a body of evidence considers within‐study risk of bias (methodological quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias.

Results

Description of studies

Results of the search

The electronic searches yielded 465 references (Figure 1). After 134 duplicate were removed the Cochrane Information Specialist (CIS) screened the remaining 331 records and removed 267 references which were not relevant to the scope of the review. We screened the remaining 64 references and obtained the full‐text reports of nine references for further assessment. We assessed the nine full‐text versions of the abstracts and all met the a priori criteria for inclusion in the final analysis. See Characteristics of included studies for details. We did not identify any ongoing studies from our searches of the clinical trials registries.


Study flow diagram.

Study flow diagram.

Included studies

We included nine studies in this review (Alberti 2001; Brahma 1996; Donnenfeld 1995; Goyal 2001; Jayamanne 1997; Kaiser 1997; Patrone 1999; Solomon 2000; Szucs 2000). The interventions compared in this review were diverse (Table 1).

Open in table viewer
Table 1. Comparator interventions of included studies

Study

Intervention 1

Intervention 2

Comparator 1

Comparator 2

Alberti 2001

Topical NSAID (indomethacin 0.1%) + topical antibiotic

None

Topical antibiotic

None

Brahma 1996

Topical NSAID (flurbiprofen 0.03%) + topical antibiotic

Topical NSAID + cycloplegic + topical antibiotic

Placebo + topical antibiotic

Cycloplegic +

topical antibiotic

Donnenfeld 1995

Topical NSAID (ketorolac 0.5%) +

cycloplegic + topical antibiotic + bandage CL

None

Cycloplegic + topical antibiotic + bandage CL

Cycloplegic + topical antibiotic + pressure patch

Goyal 2001

Topical NSAID (ketorolac 0.5%) + cycloplegic + topical antibiotic

None

Placebo + cycloplegic + topical antibiotic

None

Jayamanne 1997

Topical NSAID (diclofenac 0.1%) + topical antibiotic

None

Placebo + topical antibiotic

None

Kaiser 1997

Topical NSAID (ketorolac 0,1%) + cycloplegic + topical antibiotic

None

Placebo + cycloplegic + topical antibiotic

None

Patrone 1999

Topical NSAID (indomethacin 0.1%) +

topical antibiotic + bandage CL

None

Topical antibiotic + bandage CL

None

Solomon 2000

Topical NSAID indomethacin 1%) + cycloplegic + topical antibiotic

None

Cycloplegic + topical antibiotic + pressure patch

None

Szucs 2000

Topical NSAID (diclofenac 0.1%) +

cycloplegic + topical antibiotic

None

Placebo+ cycloplegic + topical antibiotic

None

CL: contact lens
NSAID: non‐steroidal anti‐inflammatory drug

Excluded studies

We did not exclude any study after obtaining the full text of the report.

Risk of bias in included studies

We evaluated the overall quality of each study according to the methodology detailed in Assessment of risk of bias in included studies. The Characteristics of included studies table presents different 'Risk of bias' domains. Figure 2 and Figure 3 present a graph and summary of the risk of bias of included studies.


Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Random sequence generation

Two of the studies (Brahma 1996; Donnenfeld 1995) were at a high risk of bias due to an inadequate method of sequence generation. We rated five of the studies at an unclear risk, since there was no explicit statement about the method for sequence generation.

Allocation concealment

Eight of the studies had an unclear risk of bias because there was no explicit statement about allocation concealment.

Blinding

Performance bias

In one study, the nature of the interventions was such that double‐masking was not feasible (Solomon 2000). In two of the included studies, there was no explicit statement about masking of participants or study personnel (Brahma 1996; Patrone 1999).

Detection bias

There was a high risk of detection bias in one of the studies (Donnenfeld 1995). In four of the included studies there was a low risk of bias (Goyal 2001; Jayamanne 1997;Solomon 2000; Szucs 2000). The risk of detection bias was unclear in four studies because no explicit statement about masking of outcome assessors was reported (Alberti 2001; Brahma 1996; Kaiser 1997; Patrone 1999).

Incomplete outcome data

Three of the included studies had a high risk of attrition bias (Brahma 1996; Patrone 1999; Solomon 2000).

Selective reporting

We judged all studies to have an unclear risk, since no protocol or trial registry entry was available and it was therefore not possible to assess this domain.

Other potential sources of bias

We did not identify any other potential sources of bias.

Given the relatively small number of included trials, we were unable to assess publication bias (Higgins 2011).

Effects of interventions

See: Summary of findings for the main comparison Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions

Primary outcome measures

None of the included studies reported the primary outcome measures of this review (participant‐reported pain intensity reduction of 30% or more at 24 hours and participant‐reported pain intensity reduction of 50% or more at 24 hours).

Secondary outcome measures

Use of 'rescue' analgesia (that is, oral analgesia) at 24 hours, 48 hours and 72 hours

Four studies reported 'rescue' analgesia at 24 hours as an outcome measure (Alberti 2001; Brahma 1996; Goyal 2001;Szucs 2000) (participants reported = 481). Although these studies employed different comparators (Table 1), we pooled the data, since the treatment effect was in the same direction and the results were consistent. Participants taking NSAIDs were less likely to require rescue analgesia (low‐certainty evidence); (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.34 to 0.61; Analysis 1.1; Figure 4).


Forest plot of comparison: 1 Topical NSAIDs versus placebo/standard care, outcome: 1.1 Use of rescue oral analgesia at 24 hours.

Forest plot of comparison: 1 Topical NSAIDs versus placebo/standard care, outcome: 1.1 Use of rescue oral analgesia at 24 hours.

None of the included studies reported 'rescue' analgesia at 48 hours or at 72 hours as an outcome measure.

Percentage/proportion healed after 24 and 48 hours (healing should have been ascertained using fluorescein staining or slit‐lamp examination)

One study reported the proportion of corneal abrasions that were healed after 24 and 48 hours (Solomon 2000) (participants reported = 28). Ninety‐three per cent of abrasions were healed within 24 hours and the remainder within 48 hours. There was no difference in the proportion of abrasions healed between groups (low‐certainty evidence); 24 hours (RR 1.00, 95% CI 0.81 to 1.23); 48 hours (RR 1.00, 95% CI 0.88 to 1.14; Analysis 1.2 and Analysis 1.3).

Complications of corneal abrasion (as defined by the study authors)

Six of the studies reported complications of corneal abrasion as an outcome measure (Alberti 2001; Brahma 1996; Goyal 2001; Jayamanne 1997; Kaiser 1997; Szucs 2000) (participants reported = 609). Four of these studies (Brahma 1996; Goyal 2001; Jayamanne 1997; Szucs 2000) reported no complications in either study arm. One study (Alberti 2001) reported a corneal abscess in the comparator group and one study (Kaiser 1997) reported that three participants returned with a recurrent corneal erosion (two in the control group and one in the NSAID group) (very low‐certainty evidence); (RR 0.44, 95% CI 0.07 to 2.96; Analysis 1.4).

Whether the use of concurrent topical antibiotics with additional lubricating effects reduced pain

None of the studies reported whether use of concurrent topical antibiotics (drops or ointments) with additional lubricating effects reduced pain.

Drug‐related adverse events

Two studies reported on drug‐related adverse events as an outcome measure (Alberti 2001; Jayamanne 1997) (participants reported = 163). Jayamanne 1997 reported no drug‐related events, while Alberti 2001 reported four events (three in the NSAID group, including discomfort/photophobia on instillation, conjunctival hyperaemia and urticaria and one in the control group, corneal abscess) very low‐certainty evidence; (RR 2.95 95% CI 0.32 to 27.60; Analysis 1.5).

Other adverse events (as defined by the study authors)

None of the nine included studies reported other adverse events as an outcome measure.

Discussion

Summary of main results

None of the included studies reported the primary outcome measures of this review, namely participant‐reported pain intensity reduction of 30% or more or of 50% or more at 24 hours. A 30% reduction in pain intensity represents a clinically important difference in pain severity that corresponds to patients' perception of adequate pain control (Lee 2003; Younger 2009).

Four trials that randomised 664 participants (481 reported) to receive NSAIDs or placebo/standard care reported on the use of ‘rescue’ analgesia at 24 hours as a proxy measure of pain control. These trials were associated with a reduction in the need for oral analgesia (RR 0.46, 95% CI 0.34 to 0.61).

One trial, in which 28 participants were randomised, reported on the proportion of abrasions healed after 24 and 48 hours. These levels were similar between both arms of the trial.

Two trials (163 participants randomised) reported on drug‐related adverse events, with rates low and similar between the intervention and control groups.

Overall completeness and applicability of evidence

The review has revealed a lack of high‐quality evidence to support the use of topical NSAIDs in traumatic corneal abrasion.

Quality of the evidence

Despite seven of the nine included studies being conducted following the publication of the CONSORT statement in 1996, the trials were generally poorly reported. Allocation concealment was unclear and in the absence of a protocol or trial registration it was not possible to assess reporting bias. Several of the trials were associated with missing outcome data that were sufficient to have a clinically relevant impact on the effect estimate.

Potential biases in the review process

As far as we are aware, we have minimised potential biases in the review process. We followed all methods set out in the published protocol and all potentially eligible studies were included. Assessment or risk of bias was limited by poor reporting and the absence of published protocols or trial registration.

Agreements and disagreements with other studies or reviews

A previous systematic review of topical NSAIDs for corneal abrasions (Calder 2005) included 11 RCTs, of which three were included in a meta‐analysis of self‐reported pain scores at 24 hours. NSAIDs were found to reduce self‐reported pain (weighted mean difference (WMD) ‐1.3 (95% CI ‐1.03 to 1.56)). The authors of this review concluded that topical NSAIDs can provide effective analgesia for people with traumatic corneal abrasions.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Figures and Tables -
Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Forest plot of comparison: 1 Topical NSAIDs versus placebo/standard care, outcome: 1.1 Use of rescue oral analgesia at 24 hours.
Figures and Tables -
Figure 4

Forest plot of comparison: 1 Topical NSAIDs versus placebo/standard care, outcome: 1.1 Use of rescue oral analgesia at 24 hours.

Comparison 1 Topical NSAIDs versus Control, Outcome 1 Use of rescue oral analgesia at 24 hours.
Figures and Tables -
Analysis 1.1

Comparison 1 Topical NSAIDs versus Control, Outcome 1 Use of rescue oral analgesia at 24 hours.

Comparison 1 Topical NSAIDs versus Control, Outcome 2 Proportion of abrasions healed after 24 hours.
Figures and Tables -
Analysis 1.2

Comparison 1 Topical NSAIDs versus Control, Outcome 2 Proportion of abrasions healed after 24 hours.

Comparison 1 Topical NSAIDs versus Control, Outcome 3 Proportion of abrasions healed after 48 hours.
Figures and Tables -
Analysis 1.3

Comparison 1 Topical NSAIDs versus Control, Outcome 3 Proportion of abrasions healed after 48 hours.

Comparison 1 Topical NSAIDs versus Control, Outcome 4 Complications of corneal abrasion.
Figures and Tables -
Analysis 1.4

Comparison 1 Topical NSAIDs versus Control, Outcome 4 Complications of corneal abrasion.

Comparison 1 Topical NSAIDs versus Control, Outcome 5 Drug‐related adverse events.
Figures and Tables -
Analysis 1.5

Comparison 1 Topical NSAIDs versus Control, Outcome 5 Drug‐related adverse events.

Summary of findings for the main comparison. Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions

Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions

Patient or population: analgesia in traumatic corneal abrasions
Setting: hospital emergency departments
Intervention: topical NSAIDs
Comparison: placebo/standard care

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with Placebo/usual care

Risk with Topical NSAIDs

Participant‐reported pain intensity reduction of 30%/50% or greater at 24 hours

See comment

See comment

N/A

N/A

N/A

None of the included studies reported the primary outcome measures for this review

Use of rescue oral analgesia at 24 hours

400 per 1,000

184 per 1,000
(136 to 244)

RR 0.46
(0.34 to 0.61)

481
(4 RCTs)

⊕⊕⊝⊝
LOW1

Use of rescue oral analgesia at 48/72 hours

See comment

See comment

N/A

N/A

N/A

None of the included studies reported rescue analgesia at 48 hours or at 72 hours as an outcome measure

Proportion of abrasions healed after 24 hours

900 per 1,000

900 per 1,000
(729 to 1,000)

RR 1.00
(0.81 to 1.23)

28
(1 RCT)

⊕⊕⊝⊝
LOW1

Proportion of abrasions healed after 48 hours

1,000 per 1,000

1000 per 1,000
(880 to 1,000)

RR 1.00
(0.88 to 1.14)

28
(1 RCT)

⊕⊕⊝⊝
LOW1

Complications of corneal abrasion

10 per 1,000

4 per 1,000
(1 to 29)

RR 0.44
(0.07 to 2.96)

609
(6 RCTs)

⊕⊝⊝⊝
VERY LOW1,2

Drug‐related adverse events

10 per 1,000

30 per 1,000
(3 to 276)

RR 2.95
(0.32 to 27.60)

163
(2 RCTs)

⊕⊝⊝⊝
VERY LOW1,2

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High‐certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate‐certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low‐certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low‐certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

1Downgraded two levels for limitations in study design and implementation

2Downgraded one level for imprecision (wide confidence intervals that cross the null effect)

Figures and Tables -
Summary of findings for the main comparison. Topical NSAIDs compared to control for analgesia in traumatic corneal abrasions
Table 1. Comparator interventions of included studies

Study

Intervention 1

Intervention 2

Comparator 1

Comparator 2

Alberti 2001

Topical NSAID (indomethacin 0.1%) + topical antibiotic

None

Topical antibiotic

None

Brahma 1996

Topical NSAID (flurbiprofen 0.03%) + topical antibiotic

Topical NSAID + cycloplegic + topical antibiotic

Placebo + topical antibiotic

Cycloplegic +

topical antibiotic

Donnenfeld 1995

Topical NSAID (ketorolac 0.5%) +

cycloplegic + topical antibiotic + bandage CL

None

Cycloplegic + topical antibiotic + bandage CL

Cycloplegic + topical antibiotic + pressure patch

Goyal 2001

Topical NSAID (ketorolac 0.5%) + cycloplegic + topical antibiotic

None

Placebo + cycloplegic + topical antibiotic

None

Jayamanne 1997

Topical NSAID (diclofenac 0.1%) + topical antibiotic

None

Placebo + topical antibiotic

None

Kaiser 1997

Topical NSAID (ketorolac 0,1%) + cycloplegic + topical antibiotic

None

Placebo + cycloplegic + topical antibiotic

None

Patrone 1999

Topical NSAID (indomethacin 0.1%) +

topical antibiotic + bandage CL

None

Topical antibiotic + bandage CL

None

Solomon 2000

Topical NSAID indomethacin 1%) + cycloplegic + topical antibiotic

None

Cycloplegic + topical antibiotic + pressure patch

None

Szucs 2000

Topical NSAID (diclofenac 0.1%) +

cycloplegic + topical antibiotic

None

Placebo+ cycloplegic + topical antibiotic

None

CL: contact lens
NSAID: non‐steroidal anti‐inflammatory drug

Figures and Tables -
Table 1. Comparator interventions of included studies
Comparison 1. Topical NSAIDs versus Control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Use of rescue oral analgesia at 24 hours Show forest plot

4

481

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.34, 0.61]

2 Proportion of abrasions healed after 24 hours Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3 Proportion of abrasions healed after 48 hours Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4 Complications of corneal abrasion Show forest plot

6

609

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.07, 2.96]

5 Drug‐related adverse events Show forest plot

2

163

Risk Ratio (M‐H, Fixed, 95% CI)

2.95 [0.32, 27.60]

Figures and Tables -
Comparison 1. Topical NSAIDs versus Control