Acupuncture for the management of dry eye disease

Abstract

The effectiveness of using acupuncture for dry eye disease (DED) is controversial. Thus, this systematic review investigated the effectiveness and feasibility of using acupuncture for DED in accordance with the 2020 PRISMA statement. The outcomes of interests were (1) to evaluate the efficacy of acupuncture in improving the ocular surface disease index (OSDI), Schirmer I test score, and tear breakup time from baseline to the last follow-up; (2) to determine possible complications of using acupuncture; and (3) to investigate the superiority of acupuncture over other commonly used treatments for DED. Data from 394 patients were collected. Results showed that acupuncture significantly prolonged the tear breakup time (P < 0.0001), significantly increased the Schirmer I test score ( P < 0.0001), and significantly reduced the OSDI ( P < 0.0001) from baseline to the last follow-up. Compared with the control group, the acupuncture group had significantly greater Schirmer I test score ( P < 0.0001), significantly longer tear breakup time ( P = 0.0004), and significantly lower OSDI (P = 0.002). These results suggest that acupuncture is effective and feasible in improving symptoms and signs of DED. No severe adverse effects of acupuncture were observed.

Keywords

dry eye disease / xerophthalmus / acupuncture

1 Introduction

Dry eye disease (DED) is common in adults [1]. It is a multifactorial disorder of the ocular surface, with a global prevalence up to 50% [2,3]. This disorder is characterized by an imbalance of tear production and evaporation, promoting inflammation of the ocular surface [4]. Artificial tears, lifestyle changes, topical steroids or cyclosporine, lacrimal punctal occlusion, and oral omega-3 fatty acids are commonly used to manage DED [5–10]. Acupuncture is a key component of complementary and alternative medicine [11]. Its efficacy in treating various conditions, such as low back pain, fibromyalgia, and migraine, has been investigated [11–13]. The rationale behind the potential efficacy of acupuncture in DED may involve the regulation pathways of the autonomic nervous system [14], sequentially modulating lacrimal gland function [11]. Acupuncture promotes the release of acetylcholine from nerve endings and in the lacrimal glands, thus increasing the secretion of tears [ 14,15]. Furthermore, acupuncture may increase pain threshold [16] and reduce the local inflammatory response by downregulating proinflammatory cytokines, thereby decreasing the severity of DED [17]. Previous studies have investigated the clinical effectiveness of acupuncture for DED [17–20]; however, a comprehensive literature review of such evidence is lacking. Therefore, this study investigated the effectiveness and feasibility of using acupuncture for the management of DED. We evaluated the improvement in symptoms and signs from baseline to the last follow-up, and we performed a meta-analysis comparing acupuncture with other commonly used pharmacological treatments. We hypothesized that acupuncture is reliable and feasible for DED and that its outcomes are comparable with those of other commonly used pharmacological treatments.

2 Study overview

2.1 Eligibility criteria

All randomized clinical trials (RCTs) that investigated the effectiveness of acupuncture for DED were accessed. Articles published in peer-reviewed journals in English, German, Italian, French, and Spanish, given the authors language capabilities, were eligible. Only studies with level I of evidence in accordance with Oxford Centre of Evidence-Based Medicine [21] were considered. Reviews, opinions, letters, editorials, and protocols were not considered. Animal, in vitro, biomechanics, computational, and cadaveric studies were not eligible. Only studies that investigated patients affected by DED with clinical manifestations were eligible. All types of acupuncture were considered, as were studies combining acupuncture with artificial tears. Studies combining acupuncture with other treatment alternatives were excluded. Only studies that reported quantitative data under the endpoints of interests were eligible. Disagreements between the authors were debated and mutually solved.

2.2 Search strategy

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the 2020 PRISMA statement [22]. The PICO algorithm was preliminary pointed out:

• P (Population): dry eye disease;

• I (Intervention): acupuncture;

• C (Comparison): pharmacological treatments;

• O (Outcomes): ocular surface disease index, tear breakup time, Schirmer I test score, and adverse events.

In May 2021, the following databases were accessed: PubMed, Web of Science, Google Scholar, and Embase. No time constrains were used for the search. The following keywords were used in combination: dry eye disease, dry eye syndrome, xerophthalmia, keratoconjunctivitis sicca, symptoms, acupuncture, traditional medicine, ocular surface disease index, OSDI, Tear breakup time, TBUT, Schirmer I test score, SIT, complications, andadverse events.

2.3 Eligibility criteria

Two authors (Filippo Migliorini and Julia Prinz) independently performed the database search. All resulting titles were screened and, if suitable, the abstract was accessed. The full texts of abstracts that matched the topic were accessed. A cross reference of the bibliography of the full-text articles was also screened for inclusion. Disagreements between the two authors were debated, and the final decision was made by a third author (Nicola Maffulli).

Two authors (Filippo Migliorini and Julia Prinz) independently extracted the following data: study generalities (author, year, journal, design, level of evidence, and follow-up length) and patient demographics (number of patients, mean age, and women). If the studies reported data from several follow-up appointments, only data from the last follow-up were included for analysis. Data concerning the following scores were retrieved: ocular surface disease index (OSDI) [23], invasive tear breakup time [24], and Schirmer I test score [25]. Data concerning complications were also collected. The outcomes of interests were (1) to evaluate effectiveness of acupuncture in terms of improving the OSDI, Schirmer I test score, and tear breakup time from baseline to the last follow-up, (2) to evaluate possible complications, and (3) to investigate the superiority of acupuncture over other commonly used treatments for DED.

2.4 Methodological quality assessment

The assessment of the risk of bias among the included studies was performed by one author (Julia Prinz) using Review Manger software (The Nordic Cochrane Collaboration, Copenhagen) version 5.3. The focus was on the following biases: selection, detection, performance, reporting, attrition, and other biases.

2.5 Statistical analysis

Statistical analysis was performed by the senior author (Filippo Migliorini). Improvement from baseline to the last follow-up was evaluated in terms of the mean difference (MD), standard error (SE), T value, and unpaired t-test by using the IBM SPSS software version 25. For the comparisons, the meta-analyses were conducted using the Review Manager software (The Nordic Cochrane Collaboration, Copenhagen) version 5.3. Data were analyzed using the inverse variance and MD effect measure. The comparisons were performed using a fixed-effect model. Heterogeneity was assessed through the Higgins–I2 test. If I2 test > 50%, a random-effect model was adopted. The confidence intervals (CIs) were set to 95% in all comparisons. The overall effect was considered statistically significant if P < 0.05. A funnel plot of the most reported outcome was prepared to investigate the risk of publication bias. Forest plots were created for each comparison.

3 Analysis

3.1 Search results

The literature search resulted in 155 RCTs that evaluated the effectiveness of acupuncture for DED. Of them, 77 were excluded because of redundancy. Another 64 articles were excluded because they did not match the eligibility criteria: type of study (n = 28), not focusing on the topic (n = 24), language incompatibility (n = 5), and combining with other techniques than artificial tears (n = 7). Six further studies did not report quantitative data under the endpoints of interest. Finally, 8 RCTs were eligible for analysis. The flow chart of the literature search is shown in Fig.1.

3.2 Study risk of bias assessment

Given the above-mentioned assessment of risk of bias, selection bias was considered low. A low-to-moderate attrition bias was reported overall, and performance and detection bias were at moderate risks. Twenty-five percent (2 of 8) of the included studies performed assessor and patient blinding. In the study by Dhaliwal et al., patients were not informed which treatment group they were assigned to while a blinded investigator performed all ophthalmic examinations [26]. In the study by Shin et al., patient and investigator blinding was conducted [19]. No blinding was performed in the other studies included. Thus, the risk of bias was low to moderate. The authors’ rating of each risk of bias item according to the Cochrane Collaboration is shown in Fig.2.

3.3 Risk of publication bias

A funnel plot of the most reported outcome was prepared to investigate the risk of publication bias (Fig.3). The plot evidenced adequate symmetry and estimated effects located within the pyramidal shapes. These features indicated a low risk of publication bias.

4 Explanation of new results

4.1 Study characteristics and results of individual studies

Data from 394 patients were collected, of which 75% (296 of 394 patients) were women. The mean follow-up was 13.0 ± 11.5 weeks, and the mean age of the patients was 48.4 ± 12.3 years. Generalities and patient baseline of the included studies are detailed in Tab.1.

The most common acupuncture points EX-HN5 (“Taiyang,” between the lateral canthus and the lateral end of the eyebrow [31]), BL1 (“Jingming,” above the medial canthus [31]), GB1 (“Tongziliao,” on the lateral orbital border [31]), BL2 (“Cuanzhu,” at the medial end of the eyebrow [31]), ST1 (“Chengqi,” between the inferior orbital border and the bulbus oculi [31]), and TE23 (“Sizhukong,” in the depression of the lateral end of the eyebrow [31] are displayed in Fig.4.

4.2 Effectiveness of acupuncture

The tear breakup time (P < 0.0001) and Schirmer I test score ( P < 0.0001) significantly improved from baseline to the last follow-up. The OSDI significantly reduced from baseline to the last follow-up ( P < 0.0001). These results are detailed in Tab.2.

Three studies (106 patients) [19,27,28] reported data on complications in the acupuncture group. Less than 3% (3 of 106) of the patients experienced hematoma, which resolved spontaneously.

4.3 Acupuncture compared with other treatments

The Schirmer I test score was greater in the acupuncture group than in the control group (MD 1.60; 95% CI 1.05 to 2.15; P < 0.0001). The tear breakup time was longer in the acupuncture group than in the control group (MD 1.00; 95% CI 0.44 to 1.55; P = 0.0004). The OSDI was lower in the acupuncture group than in the control group (MD −8.60; 95% CI −14.06 to −3.14; P = 0.002). These results are detailed in Fig.5.

5 Explanation of scientific significance

Main findings of the present study indicated that acupuncture is effective and feasible in improving the symptoms of DED. The tear breakup time was significantly longer and the Schirmer I test score was significantly greater in the acupuncture group than in the control group. The OSDI score was significantly lower in the acupuncture group than in the control group.

Although acupuncture is a safe procedure, some solitary cases of subcutaneous hematoma, bleeding, and needle site pain after acupuncture have been reported in the included studies [28]. However, we found no severe adverse effects of acupuncture.

In Asian countries, acupuncture has been used as a treatment option for various diseases for thousands of years [19]. The procedure involves inserting slender needles into the skin at specific locations [32]. Hundreds of acupuncture points are distributed in the human body [33]. Hypothetically, acupuncture affects organs along vegetative nerves and organs [16]. Acupuncture generally leads to a dilation of blood vessels, resulting in an increased supply of neuropeptides [19]. Concerning the eye, acupuncture has been suggested to promote the secretion of tears by the lacrimal gland and improve the stability of the tear film [20,34], stimulate corneal wound healing [35], reduce local inflammatory reactions [17], and regulate the autonomic nervous system [36]. Moreover, acupuncture has a pain-relieving effect [16]. However, the exact mechanism of effectiveness remains unclear [16]. Systematic reviews have confirmed the effectiveness of acupuncture in the management of ophthalmic conditions, such as amblyopia and optic nerve atrophy [37,38]. Recently, the effectiveness of acupuncture for DED has been investigated [27,28]. Few animal studies provided evidence of the effectiveness of acupuncture in DED. A previous study has shown that acupuncture increases the lacrimal secretion in a DED rabbit model [34]. To date, a detailed literature review of current evidence for the effectiveness of acupuncture in DED is lacking.

The World Health Organization (WHO) published “Standard Acupuncture Nomenclature” in 1993 [39]. Accordingly, acupuncture points are specified by the meridian (abbreviated by letters) and a number, which indicates its position along the meridian channel [39]. Most acupuncture points used in DED treatment are located around the eyes (Fig.4) [40]. They include EX-HN5 (“Taiyang,” between the lateral canthus and the lateral end of the eyebrow [31]), BL1 (“Jingming,” above the medial canthus [31]), GB1 (“Tongziliao,” on the lateral orbital border [31]), BL2 (“Cuanzhu,” at the medial end of the eyebrow [31]), ST1 (“Chengqi,” between the inferior orbital border and the bulbus oculi [31]), and TE23 (“Sizhukong,” in the depression of the lateral end of the eyebrow [31]) [40]. The studies included in this systematic review and meta-analysis determined acupuncture points with heterogenous criteria as displayed in Tab.1.

The results of the present study indicated that acupuncture is effective for DED. The OSDI was lower in the acupuncture group than in the control group. This score was introduced to quickly assess the symptoms of subjective ocular irritation in DED and their effects on visual related function [41]. It assesses patient-reported quality of life measures [41]. The higher the score, the more severe the DED symptoms.

Grönlund et al. investigated the use of acupuncture as a complementary treatment to artificial tears compared with a treatment of artificial tears only. Each group included 10 patients with DED. In 80% of all patients, DED was caused by Sjögren’s syndrome. Most patients were female (90% in the combined treatment group, 80% in the artificial tears-only group) [27]. The authors reported no differences in tear breakup time or Schirmer I test outcomes between the groups. However, they found subjective beneficial effects of acupuncture in the patients with DED as evaluated by a questionnaire on symptoms [27]. Moreover, Liu et al. compared the effectiveness of acupuncture plus artificial tears with that of artificial tears only in menopausal patients with DED. They reported an improvement in clinical symptoms after the combined treatment of acupuncture and artificial tears [42]. In addition, Lee et al. compared the effectiveness of acupuncture combined with usual care with that of usual care only in DED after refractive surgery. Usual care included any pharmacological supportive treatment for DED, such as artificial tears or supplements. The authors reported superior OSDI results after acupuncture treatment with usual care compared with usual care only [29]. Zhang et al. treated 30 patients with acupuncture–moxibustion and 31 patients with artificial tears. They observed a significant improvement in tear breakup time test values after acupuncture–moxibustion treatment compared with baseline but found no significant changes after treatment with artificial tears [20]. Kim et al. allocated 150 patients to either acupuncture or artificial tears treatment. Most patients were female (> 70%). DED symptoms evaluated by OSDI significantly improved after acupuncture compared with treatment with artificial tears. In addition, tear breakup time was prolonged remarkablyin the acupuncture group [28]. Tseng et al. compared the effectiveness of acupuncture and artificial tears with those of silver spike point electro-therapy with artificial tears and artificial tears only in 43 patients with DED. After 8 weeks of treatment, the acupuncture group showed greater improvements in Schirmer I test scores compared with the electro-therapy and artificial tears group. Meanwhile, no significant difference in tear breakup time was found between the groups. Altogether, current evidence suggests equal effectiveness between acupuncture and artificial tears in DED. Na et al. suggested that acupuncture combined with artificial tears might be more effective in DED than artificial tears alone [43]. Shin et al. compared the effectiveness of acupuncture with that of sham acupuncture in 42 patients with DED. Patients in the sham acupuncture control group were treated by inserting superficial needles at non-acupuncture points. They found no significant differences in OSDI, tear breakup time test, or Schirmer I test results between the acupuncture and sham acupuncture groups after 3 weeks of treatment for DED [19]. In a double-blinded trial, Dhaliwal et al. similarly compared the effectiveness of true vs. sham acupuncture. They reported a significant improvement in DED symptoms 6 months after acupuncture as assessed by OSDI, whereas sham acupuncture did not significantly improve the OSDI, tear breakup time, or Schirmer I test score [26]. The differences in follow-up length (4 weeks vs. 6 months, respectively) and acupuncture methodology between the studies by Shin et al. and Dhaliwal et al. may explain the discrepancies in the results between the two studies. Placebo acupuncture could identify the specific effects of acupuncture and sham acupuncture. However, placebo acupuncture is technically impossible. “Sham” describes any control treatment of acupuncture trying to make the patients believe they received the real treatment [11,44]. Previously, a superior effectiveness of sham acupuncture over pharmacological placebo has been presumed [45]. Even skin stimulation by non-penetrating sham acupuncture is suggested to activate sensory pathways [43]. However, with 6 months of follow-up, Dhaliwal et al. strongly suggested the treatment effectiveness of acupuncture in DED rather than a placebo effect.

In agreement with our results, previous meta-analyses and systematic reviews on the effectiveness of acupuncture in DED [11,43,46–48] found significant increases in post-acupuncture tear breakup time and Schirmer I scores. In a previous meta-analysis, no significant OSDI outcomes were reported, which can be attributed to the small sample sizes of only three RCTs considered [43]. Moreover, an improvement in corneal staining by acupuncture was reported [11,47,48]. However, some RCTs included in previous meta-analyses were unsuitable according to our eligibility criteria because they included non-RCTs [49] or actual acupuncture at non-specified acupuncture points [50]. Restricting studies based on eligibility criteria possibly reduces the heterogeneity of the included studies.

Two further RCTs investigating the effectiveness of acupuncture in DED are ongoing. One RCT (NCT04877483) at Taipei Veterans General Hospital in Taiwan aims to evaluate acupuncture on different acupuncture points (GB20 or GB20 plus BL2). Another scheduled RCT (NCT04668131) aims to compare the effectiveness between acupuncture and artificial tears in the management of DED-associated neuropathic pain. To date, both studies have not started recruiting.

6 Limitations

This study has several limitations, the most important of which was the limited study size. Given the limited quantitative data available for inclusion, different types of acupuncture cannot be analyzed separately. The control group was also heterogeneous. In the studies by Kim et al., Zhang et al., Grönlund et al., and Liu et al., artificial tears were used as treatment in the control groups; Refresh Plus® by Allergan at least once a day [18], Tears Naturale II® by Alcon, and not-specified artificial tears in two studies [17,27], respectively, were applied in the control groups. Shin et al. performed sham acupuncture at non-acupuncture points with a shallow acupuncture in patients of the control group [19]. The retrieved RCTs did not employ a placebo group. Similar difficulties are faced by studies in the surgical field because placebo surgery or placebo acupuncture is technically impossible [43].

Furthermore, some variabilities in the patient selections were evident. Liu et al. included only postmenopausal women [17], whereas adult patients of both sexes were included in the other studies. Lee et al. included patients with DED following refractive surgery within the previous 24 months [29]. Tseng et al. only included patients with a history of DED of at least 3 months, whereas Dhaliwal et al. investigated patients with persistent signs and symptoms of DED for 1 month [26,30]. However, only patients with clinically diagnosed DED based on the signs and symptoms of DED were included in all studies.

Inter-investigation variability in follow-up length also limits the reliability of our results. In addition, the repeatability of the same location of precise acupuncture points seems elusive [51], which might also limit the comparability of the included studies. Given these limitations, data from the present meta-analysis must be interpreted with caution. Future studies with level I of evidence should be undertaken to overcome current obstacles to clinical translation.

7 Conclusions

Acupuncture may be effective and feasible in improving symptoms and signs of DED. Tear breakup time was longer and Schirmer I test scores were greater while the OSDI score was lower in the acupuncture group than in the control group. No severe adverse effects of acupuncture were evidenced.

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