Dry eye, or dysfunctional tear syndrome, is a prevalent condition in the world, especially in Asia (up to 34% in one population study in Taiwan).1 Dry eye disease is significant not only because of the inconveniences and discomfort it causes in its sufferers, but also its impact on patients’ daily activities, quality of life,2 and economic burden.3 Dry eye alters the physiology of the tear film,4 disrupting the vital microenvironment, which allows the living cells of the ocular surface to function. The tear fluid also maintains the health of the ocular surface by providing it with essential nutrients and metabolites5 and acting as a barrier against microbial invasions and other insults.6 Therefore, compromised tear film integrity suggests a breakdown in ocular surface defense.
Dry eye is commonly classified by its etiology into tear deficient and evaporative forms, although neither is completely exclusive of the other.4 A decrease in aqueous tear secretion from the lacrimal gland is responsible for tear-deficient dry eye. The evaporative variant is because of excessive evaporation of the aqueous tear layer and is commonly attributed to a deficient or unstable tear film lipid layer.4,7 The lipid layer is responsible for controlling tear evaporation rate. The most common cause of intrinsic evaporative dry eye is meibomian gland dysfunction (MGD),4 which may produce deficient lipids species in the tear lipid layer.8 Abnormal lipid composition affects the physicochemical properties of the tear film, and hence its stability.8
Currently, the mainstay of dry eye treatment is topical artificial tear replacement drops. However, partly because of the lack of a lipid component in such lubricants,9 they usually provide only momentary relief for the patients. Some may even paradoxically increase tear evaporation rate.10 Tears must be applied regularly, causing further inconvenience and cost to the patients. Furthermore, constituents in tear substitutes, such as preservatives and stabilizers, may increase corneal toxicity especially when used frequently. On the other hand, eye ointment, although able to lubricate the ocular surface for a longer duration,11 significantly affects patients’ vision,12 and, therefore, are usually used just before bedtime. Theoretically, lipid-containing formulations may replace deficient lipid entities in the tear film induced by MGD. The need for a longer acting tear replacement in the management of chronic dry eye is therefore obvious.
The effectiveness of lipid-containing eyedrops, such as Refresh Endura (Allergan, Irvine, California) and Soothe (Bausch and Lomb, Rochester, New York), has been described since 1990.9 Lipid-containing eyedrops potentially have a longer-lasting lubricating effect while minimally interfering with patient’s vision.9 Lipid-containing sprays are formulations containing liposomes, which are colloidal-sized bilipid-layered vesicles. The properties of liposomes allow the encapsulation of a drug to be delivered to the site of action.13 These lid sprays, such as Tears Again Liposome Lid Spray (OcuSoft, Richmond, Texas) and Liposic (Dr. Mann Pharma, Berlin, Germany), are also available as an alternative to increase tear stability.9 In recent years, there has been growing interest in the use of lipid-containing drops, cumulating in the marketing and widespread availability of newer formulations such as Systane Balance (Alcon, Fort Worth, Texas) and Optive Advanced (Allergan, Irvine, California). Because of this trend and the recent increase in interest in evaporative dry eye and MGD research,4 it is timely to evaluate the evidence-based medicine related to lipid-containing lubricants.
In this article, we conduct a systematic review of published randomized controlled interventional studies and take into account the reliability of evidence provided by each article.
A PubMed-Entrez database search was conducted on September 29, 2011 using the terms “lipid,” “eyedrops,” “lubricant,” and “dry eye,” with the following limits applied progressively: “human,” “clinical trial,” and “randomized controlled trial.” No restrictions in languages were imposed. After reviewing the titles and abstracts of each article generated in the search, interventional clinical trials that investigated any form of lipid-containing lubricating eyedrops or lid sprays were further considered.
Any interventional trial with a control group was eligible. Trials were excluded if the study did not implement a control group without lipid-containing eyedrops/lid spray. Both crossover and parallel group methodologies were eligible, as well as randomized and non-randomized studies. For inclusion in this review, no restrictions were placed on the number of subjects, study duration, and outcome measures (including dry eye symptoms and signs as well as meibomian gland features such as occlusion of meibomian gland). The full texts of eligible articles were obtained and critically appraised by the authors. Specific predetermined information from each article was extracted by the authors.
Risk of bias was assessed using the six domains according to Cochrane’s Collaboration: (1) sequence generation, (2) allocation concealment, (3) blinding of participants, (4) blinding of outcome assessors, (5) address incomplete outcome data, and (6) selective outcome reporting. Other potential threats to the validity of the article, such as assuming the data from both the eyes of a single patient as independent data points, are also considered.14 A summary of the criteria for the judgment of each of these domains is found in a Cochrane report.14
The GRADE system (specified in section 12.2 of the Cochrane handbook) was used to evaluate the quality of the evidence presented in the trials. The level of evidence in each study was assigned as high, moderate, low, or very low.15 Randomized controlled trials represent a high level of evidence, this can however be downgraded to moderate, low, or very low depending on the presence of factors that may decrease the quality of the evidence. These factors include limitation of designs (high likelihood of bias), indirectness of evidence, inconsistency of results, imprecision of results (wide confidence intervals), or high probability of publication bias.
The search yielded 18 results, of which 11 were clinical studies conducted on the effectiveness of lipid-containing lubricants for dry eyes. Seven articles were eligible after applying the exclusion criteria (Fig. 1). Two articles16,17 were originally written in German. The English full texts for these articles were obtained. The critical aspects of each study were summarized and presented in Tables 1 and 2. Of the seven eligible studies, three investigated the efficacy of liposomal eyelid spray16–18 and the others,19–22 lipid-containing eyedrops. Six studies discussed in this manuscript recruited only dry eye patients. One study20 included dry eye and non-dry eye participants.
Two studies18,19 studied Tears Again (OcuSoft, Richmond, Texas) against a saline spray as a control, and one16 compared Tears Again with Vismed Light (TRB Chemedica International SA, Geneva, Switzerland), a hyaluronate-containing artificial tear lubricant.
Craig et al.18 evaluated the lipid layer dynamics in 22 dry eye patients for 135 min after the instillation of liposomal spray in one eye, and the other eye received placebo saline. This is a parallel group controlled study investigating signs and symptoms of dry eye. Improvement in subjective symptoms peaked at 30 min postapplication in the treated eye as reported by 70% of the participants. However, by 60 min, most subjects could not feel a difference in comfort between the treated and control eye. At 90 min, 80% of the subjects could not feel a difference in comfort from baseline. The clinical parameters similarly showed only a brief period of improvement (Table 1). Lipid layer thickness, lipid layer pattern, and non-invasive tear breakup time (NITBUT) reverted to baseline values by 90 to 135 min after application of the liposomal spray. Tear meniscus height did not change significantly with treatment. There are some concerns about this methodology, which reduced the strength of the study. First, this was a relatively small study, and there was no mention of whether the eyes had been randomized. Using the contralateral eye as a control may be problematic, as some patients may not be able to localize unilateral symptoms of irritation to one eye. For example, stinging sensation in 1 eye may be perceived by the patient as bilateral reflex watering.
In another interventional trial, symptoms and signs of dry eye were evaluated pretreatment, 10 min later, at 4 weeks and 6 months,17 382 dry eye patients were involved and divided equally into two groups, either receiving the liposomal therapy or the saline spray. Patients were recruited from a medical practitioner’s clinic and were instructed to apply the lid spray three times per day, in a double-masked manner. At the end of the treatment period, the subjects in the liposomal spray group were asked to rate the tolerance and effectiveness of the liposomal spray. As high as 93.2% of the patients rated the tolerance of Tears Again as “good” or “very good,” although 23.8% of patients experienced slight burning sensation at the initial application. Most patients (94.5%) felt that the spray was more advantageous and comfortable than their own previous artificial eyedrops. A long period free of dry eye subjective symptoms (crusty debris on the lids, burning, sandy, and dry sensation) were noticed in 44% of the patients in the treatment group, compared with 12% of the control group, although “long” was not defined in the article. Symptoms, tear breakup time (TBUT), lid margin inflammation, lid parallel conjunctiva folds, and Schirmer scores all improved as compared with the treatment group (Table 1). Among the participants, the ratio of the genders was not 50% in this study: 65.2% of the patients were female and only 34.8% of patients were male. This suggests that the study results may or may not apply to men. Although there is a big range of age among the participants (from <25 years to >60 years), there is a relatively high proportion of subjects aged >60 years. Among the women, as high as 38.6% (96/249) were >60 years old.
The third study,16 a randomized 2-center treatment study on liposomal lid spray, also found improvements in the clinical signs and subjective symptoms. Liposomal spray was compared with hyaluronate eyedrops in 216 patients with evaporative dry eye: 113 in the liposomal spray group and 103 in the eyedrop group. The lubricants were applied three times daily during a period of 12 weeks. Patients graded the tolerance and comfort of the lubricant on a 6-point scale (1 being the best and 6 being the worst). The liposomal spray was graded better by 0.9 points in both scales (p < 0.05) (Table 1). At week 4 and week 12, compared with baseline, the lid margin inflammation and the conjunctival folds improved significantly in the liposomal spray group but not the hyaluronate eyedrop group. At these time points, the NITBUTs increased more in the liposomal spray group compared with the hyaluronate eyedrop group. There was no significantly change in the Schirmer test result in both groups. There was again a higher proportion of women (n = 167) than men (n = 49). There was a disproportionately high number of elderly patients, with 64.4% older than 60 years of age.
In summary, there were 2 large studies and a small trial on liposomal sprays. However, the short-term nature (about 3 h) and contralateral eye design of one study (which was also a small study) was not helpful in determining the medium/long-term effect of the treatment. The larger studies, however, did address the signs and symptoms of dry eye and provide strong evidence for the use of liposomal spray in dry eye, especially in older people and women.
Table 2 summarizes the findings from the four studies on lipid-containing eyedrops. Goto et al.20 conducted a randomized, double-blind, placebo controlled, crossover study, comparing a homogenized oil-containing eyedrop (Soft Santear, Santen Pharmaceutical, Osaka, Japan), which is a mixture of castor oil lubricant, olyoxyethylene castor oil, sodium chloride, potassium chloride, and boric acid, against saline eyedrops as a control. After a 2-week washout period, 20 patients with non-inflamed MGD were given either treatment to be used to 2 weeks and to then switch to the other for 2 weeks of use. Subjects were instructed to instill the eyedrops 6 times daily. Severity of symptoms, tear interference grade, tear evaporation rate, corneal fluorescein staining, rose Bengal staining, TBUT, and meibomian gland orifices status improved significantly during the treatment period compared with placebo. Severity of symptoms was assessed using a subjective face score, where presence of least symptoms (smiling face) was given a score of 1, whereas the most severe symptoms (saddest face) were given a score of 9. However, it is important to note that this was a relatively small study of 20 patients, there was no washout period between treatment arms, and patients were consecutively chosen.
The second study,21 a parallel group, randomized, controlled, investigator-masked study, evaluated a 1.25% castor oil emulsion (Allergan, Irvine, California) against hypromellose (Artelac, Dr. Mann Pharma, Berlin, Germany), with 27 and 26 patients in each group, respectively. The participants were recruited by poster advertisement and qualified for the study based on the presence of at least 2 dry eye symptoms on the McMonnies Dry Eye Questionnaire and clinical signs (NITBUT or Schirmer testing). Subjects were instructed to use the eyedrops 3 times daily. At the end of the 30 days study period, clinical signs of dry eye were compared with the baseline values, without further evaluation of dry eye symptoms. These tests were done 1 to 6 h after last drop instillation. Tear evaporation rates and lipid layer structure improved significantly in the group using castor oil emulsion and in the hypromellose treatment group, but to a significantly greater extent in the castor oil emulsion group (Table 2). Tear production rates and tear osmolarity remained similar to baseline values in both groups. The study was stringent but did not evaluate patient symptoms. The age and gender composition of the study participants were not reported.
The third trial,22 a parallel group, randomized, open-label study compared Carbomer-based lipid-containing (CBLC) gel (Liposic Ophthalmic liquid gel, Bausch & Lomb, Rochester, New York) and hydroxypropyl HP-guar gel Systane Lubricant eyedrops (Alcon Laboratories, Fort Worth, Texas). There was no saline control. Thirty patients were assigned into two groups, each receiving either eyedrop and were evaluated for symptoms and signs of dry eye at baseline, 2 weeks, and 4 weeks. There was no mention of how many times per day the patients were instructed to use the drops. After 4 weeks of treatment, patients were asked to grade the efficacy of the treatment they received as excellent, good, fair, or poor. Of 15 patients, 4 treated with CBLC gel graded the efficacy as excellent, and the remaining 11 graded it as good. On the other hand, of the 15 patients treated with HP-guar gel, 2 reported excellent, 5 graded it as good, and the remaining 8 graded it as fair. Using an overall symptom score (including foreign body sensation, burning sensation, dry eye sensation, itching, and pain), there was a greater improvement in the CBLC gel treatment group than the HP-guar gel group (p = 0.004) at 4 weeks but not at 2 weeks. However, the change in the individual symptoms was not compared between the groups. The Schirmer test increased from baseline to a significantly greater extent in the CBLC gel group than the HP-guar group (p < 0.05), at 2 weeks, and at 4 weeks. However, no difference from baseline was found for TBUT in both groups. The small size of 15 patients is a drawback of the study, as well as the fact that a saline control was not used. The open-label nature (lack of masking) of the study may have added bias. As this was designed as a non-inferiority study, the conclusion was that CBLC was comparable with HP-Guar group.
Finally, Di Pascuale et al.19 studied on Refresh Endura (Allergan, Irvine, California), with saline as a control in 15 patients (5 normal subjects and 10 aqueous deficient dry eye subjects). The study lasted up to 9 h for each patient after a single eyedrop instillation. Of the 10 participants with dry eyes, 4 felt an improvement in comfort lasting 60 to 120 min in the eye receiving treatment after eyedrop instillation. On the other hand, one patient reported discomfort on usage lasting for 20 min, whereas the remaining 5 participants did not feel any difference in comfort level. None of the subjects felt any difference in comfort level in the eye receiving saline drops. Lipid layer spread time improved in the treatment group but not the control group. This study, however, was not randomized, was very small, and had no masking. The study shows the impact of the treatment on tear layer, but it does not address patient management directly because the symptoms were not evaluated. In addition, it does not address the effects of the chronic use of the medication. There were more females than males in this study (20 vs. 10).
In summary, there were 4 controlled studies using lipid-containing lubricant for the treatment of dry eye. Two of the studies show that the lipid-containing lubricant was effective in reducing the signs of dry eye without investigating symptoms, although one study evaluated the 1 time administration of drops up to 9 h only. Nevertheless, two other studies that evaluated both symptoms and signs of dry eye in a randomized and masked manner provide substantial evidence-based support for clinical use of lipid-containing drops.
Risk of Bias
The risk of bias of each study is presented in Table 3. Of the seven studies discussed, only two18,22 used a computer-generated randomization. Two studies16,21 did not state the method of randomization, two studies did not mention if subjects were randomized, and randomization was done manually by an author in one study. Only three studies17,18,20 were conducted double-masked, and none mentioned any measures taken to ensure maximal allocation concealment of the study drugs from patients.
All trials adequately addressed any missing or incomplete outcome data and were free of selective outcome reporting (Table 3). Di Pascuale et al study aimed to conduct their study on normal, as well as aqueous deficient and lipid deficient dry eye patients but only reported on normal patients and aqueous deficient dry eye patients.19
Two studies20,22 assumed that the data points from both eyes of the same patient are independent, and three studies16,17,21 did not mention how one of the two eyes had been selected for analysis. Two of the studies18,19 instilled the tested lubricant on one eye and the control in the other. This may not be ideal as application of a drug to one eye may not necessarily restrict its effects (signs and symptoms) to that particular eye, for example, parasympathetic efferent nerves may subserve both eyes.23
Strength of Evidence
All studies16–18,20–22 were randomized, controlled trials, except for one study,19 and it was unclear whether randomization had been executed in another.18 Three of the studies have been assigned “high” level of evidence, three of the studies “moderate,” and one “low.” The downgrading of the evidence in two studies18,19 is because of methodological issues (lack of randomization, small sample size). One study has been downgraded to moderate because of other methodological issues (lack of masking, and inadequate treatment in control group with use of eyedrops only three times a day),16 and another22 was downgraded to low because of indirect evidence (no measurement of symptoms) and methodological issues (very small sample size and lack of masking).
This article summarizes the evidence for efficacy of lipid-containing eyedrops and lid sprays in dry eye. They are shown to be as efficacious and safe alternatives to the conventional tear substitute in relieving the symptoms and signs of dry eye. In this manuscript, we described seven studies on lipid-containing lubricants, all of which demonstrated the efficacy of the therapy as compared with normal saline and other types of artificial tears. When compared with saline, either one lipid-containing eyedrop19 or one administration of lipid-containing spray18 provides a longer-lasting lubricating effect.
Artificial tears are the first line of dry eye therapy, most of which only target replenishing the aqueous layer. Without a lipid component in the eyedrops, it is likely that the artificial tears will evaporate just as quickly as, if not faster than, the natural tears.10 The mucous layer, though also important for stability of tears, was not addressed by lipid-containing drops.
We assessed the risk of bias of each study according to the Cochrane’s collaboration tool, and none of the studies was free of any risk of bias. Flaws in methodologies include failure to mention method of randomization, failure to mention any allocation concealment, and unmasked patient and/or examiner contributed to a weaker study, and thus, weaker evidence of the effectiveness of the therapy. In addition, two of the studies assume that the two eyes of a single patient are independent of each other, which artificially increased the sample size.24 Goto et al’s study has a prewashout but no washout between treatments.
It should also be noted that a few studies17–20 used non-preserved saline as a control, which is not usually a therapy given to patients with dry eye in most contemporary practice and therefore does not constitute the current standard of care. Although use of saline every 1 to 2 h can give palliative results, this is not the recommended frequency of use for most commercial eyedrops. It would be ethically dubious for patients to be enrolled in control groups using saline 4 times a day or less. Such comparisons are also not scientifically robust because saline differs from the lipid eyedrops by >1 component (different vehicle). The studies that compared the lipid-containing lubricant with hyaluronate,16 HP-guar gel,22 and hypromellose21 showed that lipid-containing lubricants fared better against the other formulations.
Although all other studies have shown improvements in the symptoms, tear evaporation rate, and other clinical findings, none of the longitudinal studies mentioned the amount of time between the last lubricant application and the clinical evaluation. This may also introduce bias because some patients may apply the treatment at different times before the clinical assessment. For example, if clinical assessment was done immediately after application of the lid spray, it is almost certain that there will be an increase in lipid layer thickness as compared with 9 h postapplication.
We accept that in liposomal lid spray studies, it may be difficult to ensure patient masking. In the studies comparing Tears Again and a control saline spray, masking was achieved, but the above criticism of saline still applies. On the other hand, there are no other sprays that are regularly used.
In reviews of this nature, there is an additional possibility of publication bias, as trials showing no difference may be less likely to be published. Such possibilities may be explored by looking at clinical trial databases, such as clinicaltrials.gov, but there is no way to ensure that all trials conducted have been registered or the results updated. Publication bias in the present context is less likely because of the strong and growing interest in lipid-containing lubricants.
Studies evaluated in this review have evaluated lid margin inflammation and meibomian gland obstruction, but two of the studies surprisingly did not include any clinical assessment of the meibomian glands. As meibomian gland lipids are the major contribution to the tear lipids and consequential tear stability, having a meibomian gland assessment in these trials would have increased our understanding of the pathology being treated.
We reviewed the strength of evidence that each study provided and found that the studies discussed in this article have high strength of evidence. This was not surprising, as the studies included in this manuscript were only controlled clinical trials chosen carefully by the authors. Nevertheless, the possibility of bias in these studies as discussed earlier should not be overlooked.
It should be emphasized to clinicians who read this systematic review that management of evaporative dry eye should consider the pathology in its entirety. For example, MGD has other components, such as glandular occlusion and inflammation, which need to be addressed by other modalities such as warm compresses25; omega-3 supplements26,27; macrolides such as doxycycline8,28 and azithromycin8,29; and for the more severe cases, topical cyclosporine30–32 and topical steroids.32,33
In summary, randomized controlled interventional studies have shown that lipid-containing lubricants are effective in the signs and symptoms of dry eye under certain situations. Despite the presence of some flaws in the studies reviewed, the conclusions of all the studies were clear, and there is now sufficiently strong evidence that lipid-containing lubricants can be recommended.
Singapore Eye Research Institute
11 Third Hospital Avenue
Grant support: NMRC/1206/2009, NMRC/CSA/013/2009, NMRC/TCR/002-SERI/2008 and NMRC/CG/SERI/2010 from National Medical Research Council (NMRC), Singapore, and BMRC 10/1/35/19/670 from Biomedical Research Council (BMRC), Singapore.
Received February 9, 2012; accepted July 9, 2012.
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