Efficacy and safety of manuka honey for dry eye

ABSTRACT Dry eye has become an increasingly prevalent public health issue for which there is currently no cure. Manuka honey possesses anti-inflammatory and antioxidant properties that can be used to treat dry eye. The present study aimed to systematically review evidence supporting the treatment of dry eye with manuka honey and quantify this evidence via meta-analysis. Randomised clinical trials that fulfilled the inclusion criteria from database inception until 5 September 2021, were identified through online searches of seven databases, including but not limited to Embase, Medline, and Central. Changes between the point of longest follow-up and baseline subjective symptoms, tear film quality, ocular surface characteristics, adverse events, and compliance were selected for meta-analysis. A total of 288 adult participants with dry eye from five eligible randomised controlled trials were analysed. Compared with the control groups, treatment with manuka honey demonstrated a significant improvement in Ocular Surface Disease Index, Standard Patient Evaluation of Eye Dryness, tear evaporation rate, negative conversion rate of matrix metalloproteinase-9 levels, ocular surface staining, and daily use frequency of lubricant. No serious adverse events were reported, except for temporary stinging and redness, which were generally tolerated. This review found that manuka honey demonstrated promising results for the treatment of dry eye. However, limitations of the included studies and analytical methodology affect the reliability of this conclusion. Therefore, further high-quality randomised clinical trials are required to confirm the efficacy and safety of the use of manuka honey in the treatment of dry eye.


Introduction
In 2017, dry eye was redefined as a multifactorial disease of the ocular surface caused by tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities. 1 Dry eye has become one of the most prevalent diseases in eye care, affecting millions of individuals worldwide. Its prevalence has been reported to be as high as 75% in some specific study populations. 1 Older age, female sex, Asian ethnicity, use of contact lenses, and long-term screen exposure are considered to be risk factors. 1 Intermittent to persistent eye dryness, foreign body sensation, tingling, pruritus, photophobia, blurred vision, and fluctuating vision 2 are common complaints of individuals experiencing dry eye and the main reasons for seeking medical treatment. In some severe cases, there may even be a risk for blindness due to corneal infections or ulceration. 3,4 Dry eye reduces quality of life and work efficiency, and often leads to heavy economic burden to individuals and society. 1 In addition, the inconsistency between the clinical signs and symptoms of dry eye and the lack of correlation with diagnostic tests results pose a major challenge to diagnosis and treatment. 5 There is currently no cure for dry eye, although several treatment methods exist, such as artificial tear supplementation, eyelid hygiene, punctal occlusion, and topical cyclosporine A. 1 However, these treatment methods remain far from meeting the clinical needs. Therefore, dry eye has become a public health issue that warrants attention and needs to be addressed. The industry and clinicians continue to explore new methods, approaches, and drugs for treatment.
Manuka honey is a monofloral honey collected from the Leptospermum scoparium tree, which belongs to the Myrtaceae family and is native to New Zealand and eastern Australia. 6 It contains a large amount of methylglyoxal, which imparts a unique, non-peroxide antibacterial activity. 7 In addition, compared with other types of honey, manuka honey has a higher content of polyphenolic compounds, 8,9 which lend it stronger anti-inflammatory and antioxidant properties.
Since Australia first approved the use of medical-grade honey for wound treatment in 1999, the clinical application of honey-containing wound care products has expanded to Canada, Europe, Hong Kong, New Zealand, and the United States. 10 To date, most honey products on the wound care market and those approved by the United States Food and Drug Administration are based on manuka honey solutions. 11 Two different concentrations of manuka honey, namely, Optimel Manuka+ Dry Eye Drop (Leptospermum spp. honey, 165 mg/g, Melcare Biomedical Pty Ltd, Mt Cotton, Australia) and Optimel Manuka+ Forte Eye Gel (Leptospermum spp. honey, 980 mg/g, Melcare Biomedical Pty Ltd, Mt Cotton, Australia), are regulatory approved as medical devices for treating dry eye/eye discomfort, sore eyes, and irritated eyelids. 12,13 Although several clinical trials have investigated the treatment of dry eye using manuka honey, relevant metaanalyses have not been reported. Therefore, the aim of the present study was to perform a systematic review and metaanalysis of the studies that investigated the use of manuka honey for the treatment of dry eye.

Methods
The present systematic review and meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (i.e., "PRISMA") guidelines (Table S1), 14 and the primary protocol was registered in advance with the International Prospective Register of Systematic Reviews (registration number: CRD42021275558).

Data sources and search strategy
Seven databases, including Embase (Ovid), Medline (Ovid), Central, PubMed, Web of Science, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were searched to identify potentially eligible randomised clinical trials for inclusion. The search period was from inception of the database to 5 September 2021, without any language or other restrictions. Search terms, including "dry eye", "xerophthalmia", "keratoconjunctivitis sicca", "meibomian gland", and "blepharitis", were used in combination with "honey", "Leptospermum", "Manuka", and "Optimel®". The search strategies used for the Embase and Medline databases are summarised in Table S2.

Inclusion criteria and study selection
• Randomised clinical trials with suitable data that could be extracted; • Adults (≥18 years of age) with a diagnosis of dry eye without sex or race restrictions. The following conditions were excluded: hypersensitivity, allergy to honey or bee products; active infection of the eye or adnexa; ophthalmic surgery or punctal occlusion in the past three months; systemic diseases or medications that affect dry eye, such as autoimmune diseases (Sjogren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis), certain psychiatric conditions, medication use (antihistamines, antidepressants, anxiolytics, isotretinoin, anticholinergic, diuretics, and β-blockers), 1 which are clear risk factors that aggravate dry eye; • Studies that compared manuka honey (any route of administration, oral or topical) against other treatments, such as artificial tears, placebo therapy, or no treatment; • One or more of the following outcomes were reported: Ocular Surface Disease Index, Standard Patient Evaluation of Eye Dryness, Ocular Comfort Index, meibomian gland expressibility, meibum quality, lipid layer thickness, tear osmolarity, tear evaporation rate, matrix metalloproteinase-9 levels, conjunctival/eyelid margin vascularity/redness, ocular surface staining, Schirmer test without anaesthesia, tear break-up time, 15 and adverse events.
Based on the predefined inclusion criteria, two independent reviewers (JH and LK) completed the screening and review of the studies by excluding duplicates, screening the titles and abstracts, and reading the full-texts when necessary.

Data extraction and management
Two independent reviewers (JH and MJ) used a pilot-tested data extraction form to extract the relevant information from the included studies, including name of authors, date of publication, study design, unit of randomization/analysis, sample size, intervention methods, study participants characteristics (such as age, sex, country, and aetiology), and follow-up. Changes between the longest follow-up period and baseline were selected for meta-analysis. For studies that did not directly clarify changes from baseline and studies that included ≥3 intervention groups, the standard deviations 16 and combined groups 17 were estimated in accordance with the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions. For unclear or missing information, one reviewer (MJ) contacted the corresponding author via email. The processed data were entered into Review Manager 5.4 by two reviewers (SZ, QZ), and its accuracy was checked by a third independent reviewer (JH), with disputes resolved through consensus.

Risk of bias assessment
The risk of bias was evaluated independently by two reviewers (JH and LK) in accordance with the Cochrane risk of bias tool. 18 This tool evaluates possible bias in seven domains and divides them into unclear risk, low risk, and high risk. The risk of bias plot and summary were created using Review Manager 5.4.

Data synthesis and analysis
Data synthesis and analysis were performed using the methods described in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions. 19 The mean difference (MD) with corresponding 95% confidence interval (CI) is reported for continuous outcomes, while the standardised mean difference was applied once the same outcome measures were assessed using different scales or methods across studies. Dichotomous variables are reported as risk ratio with corresponding 95% CI. The selection of fixed-effects or random-effects models for each outcome was mainly based on the number of included studies and the value of the I 2 statistic.
To minimise the deviance information criterion, a randomeffects model was selected when >3 studies were available or I 2 ≥50%. The quality of the body of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (i.e., "GRADE") approach. 20 Clinical and methodological heterogeneity across the studies was explored by analysing the details of the participant characteristics, study methods, interventions, and follow-up duration. Statistical heterogeneity among the studies was assessed using the chi-squared test and I 2 statistics. An I 2 value >70% indicated substantial statistical heterogeneity. When significant heterogeneity was observed, a sensitivity analysis was performed by removing each study one by one.
If there were sufficient evidence data, subgroup analysis was performed by severity/cause of dry eye, age/sex/race of participant, type of comparator, route of administration, and concentration of manuka honey. Since only five studies were included, reporting bias was not assessed.

Results
The literature searches retrieved 241 records, of which five randomised clinical trials 12,13,21-23 were selected for this meta-analysis ( Figure 1).

Study characteristics
The characteristics of the five included studies are summarised in Table 1. The studies were conducted in Australia (n = 3), 12,22,23 New Zealand (n = 1) 21 and China (n = 1), 13 and were all published between 2017 and 2021. All were single-centre studies. Three studies used a parallel-group design, 12,13,22 while the remaining two used a paired-eye 21 and a crossover 23 design.
With the exception of one study 13 that did not specify the unit of analysis, the remaining studies 12,21-23 had equal units of analysis and randomisation. Thus, there were no units of analysis error.
Most cases of dry eye in the trials were caused by meibomian gland dysfunction, 12,13 except for the study by Craig et al., 21 which assessed the efficacy of manuka honey among participants with blepharitis. Considering that blepharitis is a significant risk factor/cause of dry eye 24,25 and the baseline (Ocular Surface Disease Index and tear break-up time) of the study participants fulfilled the diagnostic criteria for dry eye, the study was included in the meta-analysis, and a sensitivity analysis was conducted. The participants in three studies 12,13,21 were mainly elderly individuals, with an average age of 60 years, while the participants in the other two studies 22,23 were younger, approximately 20 years of age. The proportion of female participants was higher in all included studies, which also verified that female sex is a strong risk factor for dry eye.
Manuka honey was administered in the experimental group as a constituent of eye drops, 12,13,22,23 eye gel 12 and eye creams, 21 while the intervention in the control group was mainly lubricant eye drops. 13,22,23 The duration of the five studies ranged from 2 weeks to 3 months; the sample sizes ranged from 20 to 120, and 288 participants with dry eye were included. The included studies examined the related indicators of dry eye from various aspects, such as symptomology, tear film quality, ocular surface characteristics, adverse events, and compliance. The outcome measures across studies are summarised in Table 2. Ocular Surface Disease Index, tear break-up time, conjunctival/eyelid margin vascularity/redness, and ocular surface staining were the most frequent tests.

Risk of bias assessment
A summary of the risk of bias analysis is presented in Figure 2. For selection bias, two studies 13,21 were assessed as having low risk of bias, with clear random sequence generation and allocation concealment. The remaining studies 12,22,23 were described as "randomised"; however, there was no description of how randomisation was performed. The unique colour and odour of manuka honey makes it difficult to mask participants and personnel. None of the studies were double-blinded. Studies included in meta-analysis:    Two studies were rated as high risk in attrition bias 22,23 and reporting bias, 13,21 which was caused by the high dropout rate, imbalance in missing data across intervention groups, and reported primary outcomes were not pre-specified. The reasons for being rated as having a high risk of bias were identified for other potential sources of bias. All studies were sponsored by industry (e.g., funds or drugs). A crossover design study 23 not only had no wash-out period between the two phases but also merged the data into one group for analysis. The unit of analysis was not reported in one trial. 13  Figure S1), and Symptom Assessment in Dry Eye questionnaires, while no difference was detected in the Ocular Comfort Index (MD −2.52, 95% CI −5.81 to 0.76; Figure S2) and visual analogue scale questionnaires. No significant heterogeneity was detected in any of the outcomes.

Tear film quality
The included studies evaluated the following indicators: tear break-up time, lipid layer thickness, tear meniscus height, tear osmolarity, and tear evaporation rate. Except for the significant decrease in tear evaporation rate (MD −9.41, 95% CI −17.17 to −1.65; Figure 4), there was no significant difference in tear break-up time (MD 0.44, 95% CI −0.83 to 1.71; Figure 5), lipid layer thickness (MD −1.90, 95% CI −15.21 to 11.41; Figure S3), tear meniscus height (MD −0.03, 95% CI −0.07 to 0.00; Figure S4) and tear osmolarity (MD −2.02, 95% CI −6.01 to 1.98; Figure S5) compared with the control group. Significant heterogeneity was detected in the tear break-up time (I 2 = 74%). Through sensitivity analysis, it was found that the study by Li et al. 13 was the main source of heterogeneity. After removing it, the I 2 values for tear break-up time decreased from 74% to 48%.
Subgroup analysis was performed from multiple perspectives, including study design (parallel group, others), cause of dry eye (meibomian gland dysfunction, others), region (Oceania, Asia), average age (≤50 years, > 50 years), administration site (ocular surface, periocular skin), type of comparator (lubricant eye drop, and others), and length of follow-up (≤4 weeks, > 4 weeks). The main sources of heterogeneity were the cause of dry eye (meibomian gland dysfunction, others) and region (Oceania, Asia), and the administration site may also play a role (Table 3).

Ocular surface characteristics
This part of the study evaluated outcome indicators including the Schirmer test without anaesthesia, ocular surface staining, meibomian gland function (meibomian gland expressibility score, and meibum quality score), inflammation, and microbiology of the ocular surface. Manuka honey demonstrated a significantly increased negative conversion rate of matrix metalloproteinase-9 levels (risk ratio 3.24, 95% CI 1.02 to 10.35; Figure S6) and a decrease in ocular surface staining (standardised mean difference −0.40, 95% CI −0.66 to −0.15; Figure 6), ocular Demodex and bacterial loads.
No significant differences were detected in the other indicators (meibomian gland expressibility score ( Figure  S7), meibum quality score ( Figure S8), conjunctival/eyelid margin vascularity/redness ( Figure S9), and Schirmer test without anaesthesia ( Figure S10)). Significant heterogeneity was detected in the meibum quality scores (I 2 = 89%). Sensitivity and subgroup analyses were not applicable because only two studies were included for this outcome measure.

Adverse events and compliance
The incidence of adverse events (risk ratio 7.00, 95% CI 0.88 to 55.64; Figure S11) related to manuka honey treatment was relatively high compared with the control groups (lubricant, no treatment). No serious adverse events were reported after the use of honey drops or eye cream. Most participants in the included studies demonstrated good compliance with honey treatment and reduced the daily use of lubricant eye drops (MD −1.70, 95% CI −2.71 to 0.69; Figure S12).

Discussion
This was the first meta-analysis to evaluate the efficacy and safety of manuka honey for the treatment of dry eye. Based on the combined results of the five included studies, it appears that manuka honey possesses significant benefits and promise for the treatment of dry eye, especially in the improvement of subjective symptoms. Improvement in subjective symptoms was more of a priority and consistent than the detection of dry eye signs. Since dry eye is a chronic disease, it may require a longer follow-up to observe changes in other indicators. The low cost, over-the-counter availability, sterility, absence of preservatives, long shelf-life, non-toxicity,    and minimal side effects with frequent dosing and long-term administration make manuka honey advantageous in the chronic care of dry eye. 12 Increasing evidence has shown that inflammation 1,26 and oxidative stress 27,28 are involved in the central pathological processes of dry eye. Inflammation is not only the major driving force for the sensitisation, damage, and regeneration of peripheral sensory nerves, which is related to neurobiological changes on the ocular surface, 29 it also plays a key role in the vicious cycle of ocular surface damage and is the basis of self-perpetuation of dry eye. 1 Oxidative stress and inflammation have a positive feedback regulation mechanism linked by common signalling molecules. The activation of macrophages and the respiratory burst of mitochondria during inflammation increase the production and accumulation of reactive oxygen species. Reactive oxygen species can activate several kinases (tyrosine kinase, tyrosine phosphatase, and mitogen-activated protein kinase) and transcription factors (nuclear factor-kappa B, nuclear factor erythroid 2-related factor 2, and activator protein-1) related to proinflammatory cytokines and mediators, which play a key role in the pro-inflammatory response. 30,31 In addition to dry eye, oxidative stress is also involved in the pathogenesis of various eye diseases, such as senile cataracts, age-related macular degeneration, uveitis, premature retinopathy, keratitis, and ocular inflammation. 27 Similar to the prevalence of dry eye, the levels of oxidative stress also increase with ageing. 32 Given the roles of inflammation and oxidative stress, early assessment of ocular surface inflammation and oxidative stress significantly facilitates the diagnosis and treatment of dry eye. There is no specific test to assess oxidative stress in dry eye. Conventional dry eye diagnostic methods, such as the Schirmer tear test, tear break-up time, and ocular surface staining, cannot provide direct evidence of ocular surface inflammation and oxidative stress. A recent review 33 indicated that pain, conjunctival hyperaemia/redness, mucus morphology and quality, lissamine green staining, tear osmolarity, and matrix metalloproteinase-9 levels could be used as clinical methods to assess inflammation.
Among these, the determination of matrix metalloproteinase-9 levels can be used as a direct indicator of inflammation. Matrix metalloproteinase-9 is a proteolytic enzyme produced by stressed epithelial cells on the ocular surface, 34 and its expression level in the tears of healthy subjects is 3-40 ng/ml. 5 Abnormally elevated matrix metalloproteinase-9 levels may disrupt corneal epithelial barrier function 34 and are associated with moderate to severe dry eye disease. 5 Rapid immunoassay kits are currently available for the qualitative detection of elevated matrix metalloproteinase-9 protein levels (≥40 ng/ml, positive; < 40 ng/ml negative) in tears, namely, InflammaDry (Rapid Pathogen Screening, Inc., Sarasota, Florida, United States of America), which is both highly sensitive (85%) and highly specific (94%). 5 Of the five included studies, only Albietz et al. 12 used InflammaDry to determine the matrix metalloproteinase-9 levels. The negative conversion rate of matrix metalloproteinase-9 levels (risk ratio 3.24, 95% CI 1.02 to 10.35) in the manuka honey group was significantly higher than that in the control group, implying that manuka honey is helpful for the recovery of corneal barrier function.
The reduction in ocular surface staining (standardised mean difference −0.40, 95% CI −0.66 to −0.15) also indirectly confirmed the recovery of corneal barrier function. In addition, the tear evaporation rate (MD −9.41, 95% CI −17.17 to −1.65) in the honey group decreased significantly, implying that manuka honey restored the stability of tear film, especially the lipid layer of the tear film. 35 Two studies evaluated the lipid layer thickness of the tear film. The lipid layer thickness in the experimental group in one study was significantly greater (P < 0.05) than that in the control group after 90 days of treatment with manuka eye cream, 21 while in the other it was not different from that in the control group after 28 days of treatment with manuka eye drops. 22 The recovery of lipid layer thickness may require a longer follow-up and observation period.
The ultimate goal of dry eye treatment is to restore homoeostasis of the ocular surface and tear film, which is a longterm and ongoing management process. 1 Commonly used anti-inflammatory drugs for dry eye, such as corticosteroids, cyclosporine A, lifitegrast, and tacrolimus, cannot be used for prolonged periods as they may give rise to serious adverse reactions. 36 Presently, there are few studies investigating the treatment of antioxidative stress in dry eye. However, it is not difficult to conclude from the completed randomised clinical trials 37-40 that antioxidant stress therapy has significant potential for the treatment of dry eyes. Is there a drug with anti-inflammatory and antioxidant activities, non-toxic side effects, and suitability for long-term use in the treatment of dry eye?
Honey, a natural product with complex components and rich nutrition, has both edible and medicinal properties. It consists of approximately 180-200 types of compounds, including sugars, proteins, free amino acids, essential minerals, vitamins, enzymes, and a wide range of polyphenols. [41][42][43] It has a long history as a medicine, dating back to 1900-1250 years before Christ. Three-hundred and fifty years before Christ, the famous scientist and philosopher Aristotle discussed the role of honey in treating sore eyes and wounds. 44 One of the most common therapeutic uses of honey is as a wound dressing, mainly due to its antibacterial properties. 45 The emergence of various high-efficiency antibiotics has gradually diminished the medicinal value of honey. However, with the abuse of antibiotics and the emergence of drugresistant bacteria, the call for returning to natural antibacterial drugs, especially honey, is increasing. 43,45 To date, no organisms resistant to honey have emerged. 43,46,47 Modern studies have shown that, in addition to the broad-spectrum antimicrobial (bacteria, fungi, and viruses) activity, the physicochemical composition of honey also contributes to its anti-inflammatory and antioxidative effects and stimulates tissue regeneration and wound healing. 11 Currently, it has been widely used in wound care, tumours, and metabolic and autoimmune diseases. 44,48 In eye care, honey has been used for bullous keratopathy, corneal and conjunctival inflammation, preoperative preventive medication, postoperative corneal oedema, and dry eye. 12,13 There are many varieties of honey; however, only a handful are used by the pharmaceutical industry and developed into medical-grade honey, which requires special processing and a series of strict standards. 11 Manuka honey is a typical example of medical-grade honey and has attracted extensive attention and research. In addition to its well-known antibacterial activity, numerous in vitro [49][50][51][52][53][54][55] and in vivo 54,56-59 studies have confirmed its anti-inflammatory and antioxidant properties. These studies have shown that manuka honey can inhibit the respiratory burst of neutrophils and the formation of reactive oxygen species, improve oxidative stress by activating the signalling pathway 5'-adenosine monophosphate-activated protein kinase/5'-phosphorylated adenosine monophosphate-activated protein kinase/nuclear factor erythroid-2-related factor-2, and increase enzymatic (catalase, glutathione peroxidase, and superoxide dismutase) and non-enzymatic (glutathione) activities.
In addition, manuka honey can increase the levels of the antiinflammatory cytokine interleukin-10, inhibit toll-like receptor-4 and nuclear factor-kappa B pathways, and reduce the levels of inflammatory cytokines, such as tumour necrosis factor-α, interleukin-1 beta, matrix metalloproteinase-1, matrix metalloproteinase-9, interleukin-6, and other inflammatory mediators (inducible nitric oxide synthetase). A new bioactive component (honey-vesicle-like nanoparticles) in manuka honey has been reported, 60 which could exert anti-inflammatory effects by inhibiting the formation and activation of the nucleotide-binding domain, leucine-rich-containing family, and pyrin domaincontaining-3 inflammasome. Whether there are other active ingredients in honey that have anti-inflammatory and antioxidant properties merits further discussion.
There are some issues that warrant consideration and need resolution. Given that tear hypertonicity is the main cause of dry eye, does the hypertonicity of manuka honey increase the risk of aggravating dry eye? Two studies 12,21 evaluated the effect of manuka honey on tear osmolarity. The results showed that tear osmolarity was decreased in the manuka honey group, 12,21 and the difference was statistically significant. 12 In addition to the anti-inflammatory and antioxidant effects of honey, analogous to the role of honey in wound care, 43,46,49,61 the reviewers speculated that the most direct reason may be that hypertonicity of honey draws liquids from deeper tissues to the ocular surface and forms a protective layer to keep the ocular surface moist.
Another concern is how to improve the bioavailability of honey polyphenols and explore new ocular administration routes because of the low bioavailability of honey polyphenols 62 and current ocular administration routes (topical eye drops, suspensions, gels, or creams). 4,63 In addition, the effect of manuka honey concentration and route of administration on the efficacy of dry eye requires further research. Future studies should focus on these issues.

Quality of the evidence
Except for the four outcome measures (i.e., tear break-up time, meibum quality score, conjunctival/eyelid margin vascularity/redness, and ocular surface staining), which were assessed as very low quality, the remainder were assessed as low quality. Due to the high risk of bias in blinding and other biases, all outcome measures were downgraded. Small sample size studies and/or 95% CI include a line of no effect, causing it to be downgraded for imprecision. In addition, the above-mentioned four outcome measures were downgraded by one level for inconsistency due to significant heterogeneity (i.e., I 2 > 70%) or differences in the evaluation methods and/or examination position. These findings are summarised in Table S3.

Limitations
First, only five studies were included in the meta-analysis. Both the study sample size and overall sample size were small. Second, all included studies were of low methodological quality and were rated as having a high risk of bias in ≥ 1 domain. Third, bias or heterogeneity introduced by analytical methods, such as data extraction from the point of longest follow-up, estimation of the standard deviation, combination of multi-arm studies, and selection of change-from-baseline measures for analysis. 16,19 Conclusions Dry eye is one of the most prevalent diseases in ophthalmology; however, there is no cure. Anti-inflammatory and antioxidant stress therapies may represent a breakthrough in the treatment of dry eye. Results of this meta-analysis demonstrate that manuka honey has significant benefits and promise for the treatment of dry eye, especially in the improvement of the Ocular Surface Disease Index, Standard Patient Evaluation of Eye Dryness, negative conversion rate of matrix metalloproteinase-9 levels, ocular surface staining, and daily use frequency of lubricant. Most participants demonstrated good compliance with manuka honey, and no serious adverse events were reported in any of the studies. However, limitations of the included studies and analytical methodology affect the reliability of this conclusion. Therefore, further high-quality randomised clinical trials are required to confirm the efficacy and safety of the use of manuka honey in the treatment of dry eye.