The Use of Oxymetazoline 0.1% Ophthalmic Solution for Acquired Blepharoptosis: A Systematic Review

Abstract

Objective

Oxymetazoline hydrochloride has been shown to be effective in some studies for acquired blepharoptosis and for aesthetic upper eyelid elevation. This study aims to systematically review the literature on the use of topical oxymetazoline for treating acquired blepharoptosis.

Databases Reviewed

PubMed (U.S. National Library of Medicine, National Institutes of Health), Scopus (Elsevier), and Cochrane.

Methods

A systematic review of studies published between 2013 and 2024 following PRISMA guidelines was performed using the PubMed, Scopus, and Cochrane databases. Primary outcomes included pre‐ to posttreatment change in marginal reflex distance (MRD1) after treatment with topical oxymetazoline, and mean difference (pre‐to‐posttreatment) in MRD1 versus control.

Results

Five articles included data from 458 patients for analysis. Meta‐analysis demonstrated significant improvement in MRD1 measurements posttreatment with oxymetazoline (1.40 mm; 95% confidence interval, CI [0.41 mm, 2.40 mm]). In addition, when compared to controls, patients treated with oxymetazoline demonstrated greater increase in MRD1 values (0.83 mm; 95% CI [0.10 mm, 1.55 mmm]). Heterogeneity, measured by I ² statistic, was high in all studies (85%–95%).

Conclusion

The use of oxymetazoline 0.1% ophthalmic solution significantly improves MRD1 in patients with acquired blepharoptosis. Further studies comparing this treatment in other etiologies of acquired blepharoptosis should be conducted. Laryngoscope, 135:8–14, 2025

The use of oxymetazoline 0.1% ophthalmic solution significantly improves MRD1 in patients with acquired blepharoptosis. Further studies comparing this treatment in other etiologies of acquired blepharoptosis should be conducted.

INTRODUCTION

Blepharoptosis, hereafter referred to as “ptosis,” is a condition characterized by the abnormal drooping of one or both upper eyelids, which can negatively impact the appearance of the eye and potentially the superior visual field. ¹ This may cause an asymmetric and drowsy appearance to the eye, and can be associated with anxiety, depression, concern for appearance, and diminished independence in activities of daily living. ² Blepharoptosis is thought to affect 4.7% to 13.5% of the adult population, which speaks to the widespread nature of this condition. ³

Ptosis may be present at birth or acquired later in life. Acquired blepharoptosis is further classified by etiology, including neurogenic, myogenic, traumatic, mechanical, or iatrogenic. ² The severity of ptosis is measured by Marginal Reflex Distance 1 (MRD1). This is measured with the vertical distance between the corneal light reflex to the upper lid margin. In non‐ptotic patients, MRD1 is 4 mm–5 mm, and ptosis is characterized by a measurement of less than 4 mm–5 mm. ⁴

Botulinum toxin A can be injected into the tail of the eyebrow, affecting the orbicularis oculi muscle and slightly raising the lateral brow, but this provides minimal improvement for acquired blepharoptosis. ⁴ The current standard of care for acquired blepharoptosis is surgery, which has inherent risks such as infection, overcorrection, asymmetry, recurrent ptosis, injury to the cornea, and lagophthalmos. This poses a need for an effective, noninvasive, pharmacologic treatment, which may benefit the lives of patients living with blepharoptosis.

Müller's muscle is a common surgical target that arises from the levator palpebrae superioris muscle and inserts on the tarsus, which is responsible for maintaining eyelid elevation. However, it additionally expresses adrenergic receptors which makes it a plausible pharmacologic target. ² Oxymetazoline hydrochloride, 0.1% ophthalmic solution (RVL Pharmaceuticals Inc, Bridgewater, NJ) is a novel, sympathomimetic, pharmacologic agent that was recently approved in 2020 for the treatment of acquired blepharoptosis, making it the first drug approved for this condition. Previous studies ² , ³ , ⁴ , ⁵ , ⁶ have shown that oxymetazoline is an effective medical treatment for acquired blepharoptosis; however, these studies are typically single‐center studies with limited sample sizes. To our knowledge, no study has been performed compiling the current data on this topic to determine efficacy and validity of the studies. The purpose of this study is to systematically review current literature on the efficacy of oxymetazoline for treating acquired blepharoptosis. We hypothesize that oxymetazoline will significantly increase the MRD1 in patients with acquired blepharoptosis.

MATERIALS AND METHODS

Search Criteria

This study adhered to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. ⁷ To identify studies for inclusion in this review, detailed search strategies were developed for the following three databases: PubMed (U.S. National Library of Medicine, National Institutes of Health), Scopus (Elsevier), and Cochrane (Cochrane). Databases were searched from the date of inception through May 2024. The search strategies used a combination of subject headings (e.g., MeSH in PubMed) and keywords for the following two concepts: “Oxymetazoline” and “blepharoptosis.” The PubMed search strategy was modified for the other two databases, replacing MeSH terms with appropriate subject headings, when available, and maintaining similar keywords. References were imported into the review management software, Rayyan, ⁸ for study selection.

Selection Criteria

Using PICO(S) framework, we included studies that assessed patients with ptosis who were treated with oxymetazoline ophthalmic drops, as compared to those treated with a non‐pharmacologically active lubricating drop, and measured improvement in MRD‐1 during the time in which the drops used were included. ⁹ Studies assessing the effect of using oxymetazoline hydrochloride were included. Studies were considered for inclusion if they were: (1) double‐ or single‐blinded randomized controlled trials, (2) double‐ or single‐blinded randomized comparison trials, (3) non‐randomized controlled trials, and (4) prospective or retrospective observational studies. These articles also included patients 18 years or older with a known diagnosis of synkinesis and acquired blepharoptosis or blepharospasm, including blepharoptosis secondary to botulinum toxin or myasthenia gravis. Exclusion criteria included: pediatric study population, presence of otologic disease, non‐English language, nonhuman studies, review articles, case reports, duplicates, inaccessible articles, incomplete or missing statistical data, intravenous oxymetazoline use, and cutaneous oxymetazoline use. There were no restrictions on country, race, sex, or date of publication. Abstracts were first independently assessed by two reviewers (M.N. and H.E.) to identify all articles that met the inclusion criteria. Conflicts were resolved by a third reviewer (C.M.).

Included articles were critically appraised to assess level of evidence using the Oxford Center for Evidence‐Based Medicine criteria. ¹⁰ The risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions version 6.0. ¹¹ The Risk of Bias in Non‐Randomized Studies‐of Interventions (ROBINS‐I) tool was used specifically to evaluate non‐randomized studies. ¹¹ Two authors (M.N. and H.E.) performed a pilot assessment on three studies to check for consistency of assessment, both then performed independent risk assessments on the remaining studies. Any conflicts were resolved by a third reviewer who was blinded to the initial assessment. Risk of bias items included the following: bias due to confounding, bias in selection of participants into the study, bias in classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in measurement of outcomes, and bias in selection of the reported results. The risk of bias for each aspect was graded as low, moderate, or high.

Data Extraction

Data extraction was performed by two reviewers (M.N. and H.E.) independently. Data extracted from studies included demographics (patient age, sex), type of intervention (oxymetazoline, Botox, control), pre‐ and posttreatment MRD1, and mean difference in pre‐ and post‐MRD1. In instances of incomplete data, two attempts were made to contact the primary author via email for clarification or sharing of primary data.

Statistical Analysis

Meta‐analyses of continuous measures (comparison of means and standard deviations) between pretreatment and posttreatment groups as well as difference in pre‐/posttreatment versus controls were performed with Cochrane Review Manager (RevMan) version 5.4 (The Cochrane Collaboration, 2020). Under the random‐effects model, the true effects in the studies are assumed to vary between studies, and the summary effect is the weighted average of the effects reported in the various studies. ¹² The random‐effects model provides a more conservative estimate (i.e., with a wider confidence interval [CI]). When heterogeneity was present, the random‐effects model was preferred. A p‐value of <0.05 was considered to indicate a statistically significant difference for all statistical tests. A funnel plot or Egger's test was not conducted to assess for publication bias because less than 10 studies were included, so there was not sufficient power for either of these tests.

RESULTS

Search Results and Study Characteristics

A total of 157 unique publications were collected in the literature search. Screening by title and abstract excluded 143 articles. Detailed full‐text review excluded another nine, leaving a total of five articles for inclusion in the final analysis. ² , ³ , ⁴ , ⁵ , ⁶ Figure 1 provides a summary of the search process. The risk of the bias graph is summarized in Figure 2, and it shows the majority of studies were considered low for overall risk of bias with the exception of Bernardini et al.

Fig. 1.

Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) flow diagram. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

Fig. 2.

Risk of bias graph: review authors' judgments about each risk of bias item across all included studies. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

The five included articles were published between 2020 and 2023. Studies included two case reports/case series, one randomized controlled trial, one prospective cohort study, and one clinical trial. Direct measurement of MRD1 was used in all included studies. Based on the Oxford Levels of Evidence, the included studies had levels of evidence ranging from 2 to 4. Study characteristics are summarized in Table I.

TABLE I.

Descriptive Features of Included Studies.

Author (Year)	Country	OLE	Study Design	Outcome Assessed	Total Patients (n)	Mean Age (SD)	Male (n)	Female (n)
Bernardini (2023)	USA	4	Case series	MRD1	8	42.1 (7.75)	0	8
Safi (2021)	USA	4	Case series	MRD1	3	63.0 (3.46)	2	1
Shoji (2023)	USA	2	RCT	MRD1, FACE‐Q, Validated Bulbar Scale	114	31.3 (10.1)	37	77
Slonim (2020)*	USA	2	RCT	MRD1, Leicester peripheral field test, adverse events	304	Oxymetazoline group: 64.1 (13.4)	82	222
						Test group: 63.3 (14.7)
Ugradar (2022)*	USA	3	Prospective	MRD1	29	Male: 39 (9)	9	20
						Female: 46 (5)

^*These studies reported mean age and SD separately, and have been tabulated separately to preserve accurate reporting.

OLE = Oxford Levels of Evidence; RCT = randomized controlled trial; SD = standard deviation.

Patient Characteristics

Overall, 458 patients were represented in our included studies. Mean age was reported by all five studies and ranged from 31 to 65 years with an overall mean age of 45.5 years. ² , ³ , ⁴ , ⁵ , ⁶ Sex distribution as reported by all studies (n = 5) showed our analysis included 130 men (28.4%) and 328 women (71.6%).

Meta‐Analysis Results: Mean Reflex Distance 1

Five studies examined the change in MRD1 in patients treated with oxymetazoline. Meta‐analysis of pre‐ and posttreatment MRD1 demonstrated a significant improvement (1.40 mm; 95% CI [0.41 mm, 2.40 mm]). In addition, when compared to controls, patients treated with oxymetazoline demonstrated greater increase in MRD1 values from pretreatment baseline (0.83 mm; 95% CI [0.10 mm, 1.55 mm]). The results of the meta‐analysis are summarized in Figures 3 and 4.

Fig. 3.

Meta‐analysis of mean difference of mean change in MRD1 in pre‐ and posttreatment measures between oxymetazoline group versus control group. CI = confidence interval; MRD = mean reflex distance; SD = standard deviation. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

Fig. 4.

Meta‐analysis of mean difference between pre‐ and posttreatment MRD1 in patients treated with oxymetazoline. CI = confidence interval; MRD = mean reflex distance; SD = standard deviation. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

Qualitative Outcomes

In addition to quantitative measures such as MRD1, there are qualitative outcomes that are valuable in determining the efficacy of this medication. Bernardini et al. reported “patient satisfaction” among their participants, to which all reported a “high” level of satisfaction. Shoji et al. noted that patient‐perceived eye appearance was significantly improved in the treatment group as compared to the control, in terms of increased eye size and decreased eye redness. Eye redness was measured through the Validated Bulbar Scale, which depicts 10 reference images that patients grade on a scale of 10 to 100, with 10 being mild redness 100 being severe redness. The oxymetazoline group reported a 10.5 out of 100 versus 11.6 in the control group (p = 0.0002). This article also reported patient reported appearance using FACE‐Q, which is a validated patient reported questionnare commonly used cosmetic and facial surgeries to assess for patient satisfaction. It is comprised of multiple scales that measure appearance, health related quality of life, and adverse events. Patients rated their satisfaction with a numeric scale of 0–28, with higher scores correlating to a higher level of satisfaction. Prior to the use of oxymetazoline, the test group reported a score of 21.1, and the control group reported a score of 22.7. After the use of oxymetazoline, the scores were 24.4 and 23.5, respectively (p = 0.0002). Slonim et al. also investigated the change in peripheral vision through the Leicester Peripheral Field test, which is a validated visual field test to assess for superior visual field loss due to ptosis. They found that, when compared to placebo drops, oxymetazoline resulted in a significant improvement in the number of points detected on visual field testing (mean difference: 4.07 dots; 95% CI [2.74, 5.39]).

DISCUSSION

The results of this study suggest that oxymetazoline is an effective medical treatment for acquired blepharoptosis. After application of oxymetazoline, MRD1 improved significantly compared to pretreatment baselines in all included studies. Additionally, when compared to MRD1 change in placebo controls, oxymetazoline produced a statistically significant greater change in MRD1. This suggests that the observed change is solely due to the pharmacological action of the drug. These findings are relevant in light of the lack of efficacious medical treatments available for acquired blepharoptosis. As surgical correction is associated with a number of potential complications including infection, overcorrection, under correction, recurrent ptosis, corneal injury, bleeding, and lagophthalmos, this is especially important for patients who may be hesitant to undergo surgery. ¹³

Apart from aesthetic eyelid drooping as measured by MRD1, blepharoptosis may also be associated with visual field deficits that can significantly affect quality of life and function. ¹⁴ While the results of our study would suggest that improvements in MRD1 may also lead to improvements in visual field deficits, there are simply not enough current studies to demonstrate this via meta‐analysis. Slonim et al. reported statistically significant improvement in the mean number of points visualized on the Leicester Peripheral Field Test in the oxymetazoline group compared to the placebo group (mean difference: 4.07; 95% CI [2.74, 5.39]). ² These results are encouraging and should continue to guide future areas of study.

There are a limited number of available medical therapies for blepharoptosis with various levels of efficacy. First‐line conservative management generally involves a combination of neuromuscular retraining and chemodenervation, which aims to optimize voluntary muscle control and selectively weaken muscles contributing to asymmetry. ¹⁵ , ¹⁶ Botulinum is shown to have a significant increase in MRD1—Ludwig et al. showed that patients with ptosis had a baseline MRD1 of 2.00 ± 1.13 mm, and after treatment, their MRD1 increased to 2.52 ± 1.13 mm. ¹⁵ While this improvement is more significant than that seen with oxymetazoline drops, there are downsides that may deem this treatment option undesirable, such as frequency of readministration or incomplete results. This may encourage patients to seek further treatment. At this point, surgery would be considered. External levator advancement (ELA) or Müller's muscle conjunctival resection (MMCR) are surgical options for patients with mild‐to‐moderate blepharoptosis that do not respond to conservative treatments. ¹⁷ Both have been found to significantly improve MRD1 with certain studies advocating that MMCR is the superior option. ¹⁸ , ¹⁹ Specifically, the improvement in MRD1 in postoperative ELA patients was 2.6 versus 3.18, p = 0.047, but was not statistically significant at 3–6 months postoperatively. Patients who underwent MMCR had higher success rates and lower rates of under correction, making this a more desirable procedure for some. Additionally, a systematic review was performed that investigated the mean improvement in MRD1 among aponeurotic surgery, Müller muscle resection, frontalis suspension, and levator resection, which are other options for surgical correction of ptosis. ²⁰ The mean improvement in MRD1 was 2.15 ± 0.90 mm. While oxymetazoline does not produce a significant improvement, it has potential as an adjunct treatment, or can be used to replace the downsides of surgery.

As previously discussed, surgery carries an inherent level of risk including eyelid asymmetry, infection, keratopathy, hemorrhage, and loss of vision. ²¹ Comparatively, the safety profile of oxymetazoline has been explored and initial results are reassuring. Wirta et al. performed a pooled analysis of multiple randomized, placebo‐controlled studies that assessed for safety and efficacy of oxymetazoline. Their results showed that when compared to non‐active placebo ophthalmic drops, oxymetazoline had a similar adverse event profile and good tolerability with long‐term use. ¹

There are various etiologies of blepharoptosis, and determining the etiology is important in guidance to the appropriate treatment. One of these etiologies is botulinum toxin induced ptosis, for example, in the correction of blepharospasm. ²² This is thought to be due to the local spread of toxin to the levator palpebrae superioris muscle. Not only is oxymetazoline effective in correcting this adverse side effect, but it is also effective in reducing blepharospasm in combination with botulinum A. ²³ Sung et al. demonstrated in a case series that the addition of oxymetazoline, both alone and in conjunction with botulinum A injections, causes a clinically significant reduction in blepharospasm. The role that oxymetazoline plays in the primary or adjunctive treatment of this condition and its position in the ladder of escalating interventions is still being discovered. Future research is needed to better characterize its effectiveness both in conjunction with and compared to currently established treatments for other etiologies of acquired blepharoptosis.

This study has a number of limitations. Being a systematic review, data are collected retrospectively from published articles which might introduce bias inherent to the studies. Additionally, these studies have significant heterogeneity, which was a major limitation to this study. The studies included were case reports, randomized controlled trials, and a prospective study—these study designs all vary greatly in their methodology, and therefore pose heterogeneity as a risk and may confound results. For example, the studies by Shoji and Slonim compared oxymetazoline to a vehicle drop, while the other studies did not utilize a control drop. These studies also included patients with different severities of ptosis, which may lead to variables in the difference in MRD1. Additionally, the included studies did not report prior treatments for ptosis, which may affect the efficacy of the drop and reported outcomes. The etiology of ptosis may vary among studies as well; Bernardini et al. reported oxymetazoline in botulinum induced ptosis, whereas other studies investigated the use of this medication in ptosis more broadly. This is a significant limitation to this study, and likely due to the novelty of this medication and lack of background research on this subject.

An analysis of bias showed that the majority of included studies had a low risk of bias, except for one, which had a moderate risk of bias, in all categories.

Additionally, non‐English studies were excluded as a part of the screening criteria, which could exclude a number of relevant studies from the analysis. MRD1 is measured from upper eyelid margin to the light reflex on the patient's cornea, typically done with the patient looking straight forward in a neutral gaze and head position. Despite this, measurements are operator dependent and variable, which may introduce over‐ or underestimation of treatment effect. Measurements may also be affected by situational factors known to affect the degree of upper eyelid descent (e.g., time of day, eyelid fatigue, severity of blepharospasm). Despite our analyses showing statistically significant improvement in MRD1 following treatment, this only demonstrates efficacy of treatment. None of the included studies compared oxymetazoline to current treatments for blepharoptosis, and instead used non‐medicated drops for the control group, limiting conclusions that could be drawn regarding its non‐inferiority to other therapies. This is likely because oxymetazoline was only recently approved by the United States Food and Drug Administration (FDA) in 2020 for treatment of blepharoptosis, giving investigators only a short period of time to investigate the drug since its approval.

CONCLUSION

This systematic review and meta‐analysis supports the efficacy of oxymetazoline 0.1% ophthalmic solution for the treatment of acquired blepharoptosis. This finding is significant, as it is the only approved pharmacologic option for this condition. Although this data is applicable to patients with acquired blepharoptosis, there is limited data on the efficacy of oxymetazoline as an adjunct therapy for other causes of blepharoptosis, such as periocular synkinesis, neuromuscular disorders, traumatic or iatrogenic ptosis. Further research is warranted to further elucidate the use of oxymetazoline topical drops in these conditions.