Study registration
This protocol complies with the 2015 Preferred Reporting Project Guidelines for Systematic Reviews and Meta-Analysis Protocols. It is officially registered (registration number CRD42023487570) in the International Prospective Register of Systematic Reviews (PROSPERO).
Inclusion criteria
Types of studies
This study protocol exclusively includes RCTs focusing on the acupuncture treatment for DED patients with NP symptoms. Quasi randomized clinical trials and duplicate publications will be excluded from this protocol. There will be no limitations regarding the language or publication status of the included research.
Types of participants
The participants in this study will include patients diagnosed with DE in accordance with the diagnostic guidelines established by the Tear Film and Ocular Surface Society (TFOS, 2017) [53]. Additionally, patients exhibiting typical symptoms of NP, such as "spontaneous pain," "burning sensation," "dysesthesias," "allodynia," and "hyperalgesia" [20].
The age, gender, and ethnic group of enrolled participants will not be limited. Patients meeting any of the following risk factors for their DE symptoms will be excluded: (1) a history of contact lens use; (2) the use of ocular medications but not artificial tears; (3)systemic drug effects, autoimmune disease, and refractive surgery [3, 54-57];(4) presence of an active external ocular process; (5) a history of cataract surgery within the last 6 months; (6) a history of glaucoma or retinal surgery [58];(7) the presence of diseases in the conjunctiva, cornea, tear duct, iris, and meibomian gland, et al. [59].
Outcome measurements
Primary outcomes
The evaluation of ocular surface function and severity of NP will be conducted using a set of established scales [60], including the Schirmer’s I test (SIT), tear breakup time (TBUT), ocular surface disease index scores (OSDI), NP Symptom Inventory modified for the Eye (NPSI-Eye), as well as the Ocular Pain Assessment Survey (OPAS). The specific procedures are outlined as follows:
(1) SIT: This test is used to assess tear secretion and has been widely acknowledged as an authoritative measure in ophthalmology. The procedure involves placing a filter paper strip into the patient's lower eyelid conjunctiva, removing it after 5 minutes, and measuring the length of the wet paper. A measurement of less than 10mm is considered abnormal [2].
(2) TBUT: TBUT is a reliable indicator for evaluating the stability of the TF. It is used to measure the duration until the initial appearance of a black spot to on the fluorescein-stained TF post blinking [24].TBUT can be categorized into fluorescein TBUT (FTBUT) as well as non-invasive TBUT (NITBUT).
(Ⅰ) FTBUT: The fluorescein will be immersed into the conjunctival sac, and the patients will be instructed to blink certain times, then the evaluation of TF will be conducted under a microscope utilizing a cobalt blue filter. We will observe and record the time it takes for fluorescein to evenly distribute from the first TF rupture. We will repeat this operation three times and take the average of the obtained data. An FTBUT of less than10s will be considered abnormal [2].
(Ⅱ) NITBUT: NITBUT will be measured by Oculus K5M. By monitoring the condition of the TF through infrared radiation and using the Oculus algorithm, the time, as well as the location of TF rupture were obtained. A NITBUT less than 10s will be considered abnormal [61].
(3) OSDI: OSDI, recognized as one of the most authoritative questionnaires, not only measures symptoms and their frequency but also evaluates the impact of environmental triggering factors and vision on quality of life [62]. The 12 questions of OSDI are categorized into ocular discomfort, vision-related functions, and environmental factors. The frequency of symptoms determines the score assigned to each problem, ranging from 0 to 4. Patients with a total OSDI score of ≥ 13 will be considered to have symptoms of DE syndrome. The higher the score, the greater the severity of symptoms will become [53, 63].
(4) NPSI-Eye: Specifically designed for NP [58], NPSI-Eye consists of 12 questions, each scoring from 0 to 10. A higher total score corresponds to a greater level of symptom severity in individuals with NP.
(5) OPAS: OPAS is a validated tool for assessing the intensity of eye pain[64], comprising 32 questions in 8 fields. Each question is scored on a range of 0-10 or 0-100, where a higher score corresponds to a greater level of symptom severity [64].
Secondary outcomes
Secondary outcomes will involve the scores of visual analogue scale (VAS) corresponding to ocular symptoms as well as acupuncture-related adverse events (AEs):
(1) VAS: This method allows patients to self-assess the severity of eye pain by marking a 10-centimeter line, where one extremity denotes the absence of no pain while the opposite end represents the maximum of pain [65].
(2) AEs: Data will be recorded and analyzed regarding the summary / proportion of AEs linked to acupuncture, including incidents like syncope as well as hematoma [66].
Interventions
The treatment group will receive either acupuncture alone or acupuncture combined with routine treatment. Specifically, RCTs involving traditional Chinese medicine, ear acupuncture, as well as other combined treatments were included. On the other hand, the control group will receive standard treatments, like artificial tears, anti-inflammatory medications, antiepileptic drugs, TCAs, as well as opioid antagonists. The selection of acupuncture points / type / depth (electroacupuncture or manual acupuncture) as well as the frequency and duration of acupuncture treatment, will not be restricted.
Search strategy
Electronic searches
Recently, the NP symptoms have received increasing attention in patients with DED . To ensure that the evidence reflects the most recent advancements and understanding of NP symptoms in patients with DED, and make sure the reliability of the findings presented in this systematic review , we will limit our article search to those published within the last decade (1 January 2014 to 31 December 2023) , focusing on the following keywords: ‘acupuncture’, ‘acupunct’, ‘Acupuncture therapy’, ‘electroacupuncture’, ‘electroacupuncture therapy’, ‘acupoint’, ‘needling’, ‘manual acupuncture’, ‘dry eye’, ‘disease’, ‘xerophthalmia’, ‘DE’, ‘DED’, ‘DES’, ‘NP’, ‘neuropathic ocular surface pain’, ‘neuropathic ocular pain’, ‘ocular NP’, ‘neuropathic corneal pain’, and ‘chronic NP’. The search will involve 4 English databases (PubMed, Cochrane Library, Embase, and Ovid), 3 Chinese databases (China National Knowledge Infrastructure, Wanfang, Chongqing VIP Information), 3 Japanese databases (Japan Science, Technology Agency and Japan Medical Abstracts Society), as well as 3 Korean databases (Korean Medical Database, Oriental Medicine Advanced Searching Integrated System, and Research Information Service System). We will not restrict language or publication dates. In addition to electronic searches, the lists of selected articles will be screened independently to identify any omitted studies. Table 1 shows the search strategy for PubMed.
Other search resources
For further resources, we will check the reference lists of all included RCTs alongside reviews for additional studies. Besides, the International Clinical Trial Registry Platform from the World Health Organization, China Clinical Trial Registration, as well as ClinicalTrials.gov will be searched to include planned, ongoing, or unpublished studies. Additionally, grey literature will be retrieved through google.
Study selection
All studies will undergo independent evaluation by 2 researchers (QW and YZ), and inconsistencies evaluation results will be resolved through discussion. In the event of disagreements, a third researcher will be involved as a mediator to facilitate process of reaching a consensus. The process for selecting research will be illustrated in online supplemental Figure 1 of appendix 1, on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram 2020 [67].
Data collection and analysis
Upon full-text review of selected articles, two researchers (SW and GZ) will independently extract the following information:
(1) Baseline details of articles (such as first author, country, as well as the language used).
(2) Base features of the study population (including sample size, diagnostic guideline, efficacy criteria, as well as demographic baseline).
(3) Details relevant with treatment / control groups (intervention measures, treatment duration, along with the frequency).
(4) Details on the methods (blinding together with allocation concealment).
(5) Study outcomes (such as primary outcomes involving SIT, TBUT, FL, OSDI, NPSI-Eye, along with OPAS; secondary outcomes involving VAS along with AEs). Any unclear data will be resolved by promptly contacting with authors, and disagreements would involve intervention from a third independent researcher.
Assessment of the risk of bias
Two authors (QW together with YZ) will independently evaluate the risk of bias utilzing the 'risk of bias' tool [68, 69]. Studies that are considered eligible for systematic review will undergo comprehensive evaluation, involving the concealment of allocation, blinding of participants, blinding of outcome assessments, incompleteness of outcome data, selective reporting of outcomes, as well as other biases. Subsequently, the assessment results were categorized as low, high, or unclear risk.
Missing data
Efforts will be made to obtain missing information from included studies by contacting the original researchers through email/phone. Studies with unobtainable information will be excluded.
Assessment of heterogeneity
The assessment of heterogeneity among included studies will be performed utilizing χ2 and I2 tests [68]. A statistically significant heterogeneity will be indicated by χ2 test p values less than 0.10. The value of I2 will be assessed using a four-level scale [68] to determine the extent of heterogeneity. Subgroup analysis will be conducted if heterogeneity was identified.
Assessment of reporting biases
Funnel plots will be employed to demonstrate potential reporting bias in studies exceeding ten.
Data synthesis
Given the potential variance in populations among the included randomized controlled trials, a random-effects model will be adopted to conducted a meta-analysis using RevManV.5.3.5 software. To assess the acupuncture’s effectiveness in treating patients with DE in conjunction with NP, continuous data will be presented as the weighted mean difference with a 95% Confidence Interval (CI), and analyzed utilizing the inverse variance method; while the dichotomous data will be described with the risk ratios with a 95% CI and analyzed utilizing the Mantel-Haenszel method [68]. In case that the unavailability of meta-analysis, researchers may adopt a narrative and qualitative summary as an alternative.
Subgroup analysis
Subgroup analysis will be conducted based on potential factors to explore heterogeneity, including different acupuncture methodologies, various assessments of TBUT, diverse formulations of artificial tears, the selected points for acupuncture, the duration of treatments, age, sex, severity of NP, as well as the duration of DE symptoms.
Sensitivity analysis
Sensitivity analysis will be used to assess the validity along with the reliability of pooled outcomes. Potential low-quality studies will be subject to sensitivity analysis, and trials with high bias risk will be omitted and excluded. Additionally, the influence of the chosen model will be duly considered.
Summary of findings
The summary of findings will be presented in a table created by the Grading of Recommendations, Assessment, Development, and Evaluation Grading Explorer (GRADEpro) system. The quality of evidence will be independently evaluated by two authors (JW and QG) on a basis of 5 criteria, including risk of deviation, inconsistency, indirectness, imprecision, as well as publication bias. Four ratings (high /medium /low /very low) will be assigned to each criterion.
Ethics and dissemination
As we will not collect or generate raw data, ethical approval is deemed unnecessary for the present study. Our research findings will be disseminated via journals subjected to peer review.
Patient and public involvement
Neither patients nor the general public will be engaged in the design, reporting, or dissemination of this research.Registration details、consent to Participate declaration and the Clinical Trial Number is deemed unnecessary for the present study.
Human Ethics and Consent to Participate declarations: not applicable.