A Systematic Review and Meta-Analysis of Acupuncture Treatment for Oral Ulcer

Background Oral ulcer (OU) is a common oral mucosal disease manifested with obvious pain. In some studies, the efficacy of acupuncture in OU has been confirmed, but systematic reviews and meta-analyses for them are lacking. Our aim is to evaluate the efficacy of acupuncture in the treatment of OU. Methods We searched the literature from eight databases from their inception to December 2021. We included randomized controlled trials of acupuncture for the treatment of oral ulcer. The meta-analysis was carried out using Review Manager 5.3 and Stata 16.0. The main outcomes were the effective rate and the recurrence rate, the secondary outcomes were the visual analogue score (VAS) and the ulcer healing time. Results Totally, 18 studies were finally included in the meta-analysis, including 1,422 patients. In meta-analyses, we found that in comparison with Western medicine, acupuncture can improve effective rate (OR = 5.40, 95% CI: 3.40 to 8.58), reduce the ulcer recurrence rate (OR = 0.21, 95% CI: 0.13 to 0.33), and relieve the ulcer pain (MD = −2.26, 95% CI: −4.27to−0.24). In addition, compared with Western medicine, acupuncture plus Western medicine also can improve effective rate (OR = 2.95, 95% CI: 1.48 to 5.85). Compared with the Chinese medicine, the acupuncture plus Chinese medicine can improve the effective rate (OR = 8.26, 95% CI: 3.61 to 18.88) and relieve the ulcer pain (MD = −1.85, 95% CI: −2.51 to −1.19). Conclusion Acupuncture may be more effective than Western medicine in terms of efficacy rate, and acupuncture combined with Western or Chinese medicine may have the potential to reduce the recurrence of ulcer and relieve the ulcer pain. However, due to limited evidence, higher quality and more rigorously designed clinical trials with larger sample sizes will be needed to further confirm our findings.


Introduction
Oral ulcer (OU) is the most common disease of oral mucosal all over the world [1,2].Among the gobal population, the incidence of OU is 5% to 20% [3,4].Te clinical manifestations of OU are recurrent round or oval ulcers covered with yellow or grayish white pseudomembrane which are surrounded by a hyperemic red halo of about 1 mm.Te central sunken of the ulcer has a soft base and obvious burning pain [5,6].Mild patients experience ulcer attack once a few months, while serious patients experience it all the time.Although the lesion does not bring serious damage to the body and can heal itself, the pain and discomfort caused by OU contribute unease to eating, drinking, teeth brushing, and even speaking, leading to a decline in the patient's quality of life and work efciency [7,8].
Presently, the etiology and pathogenesis of OU are not clear.Current studies believe pathogenic factors may include immune, gene, local trauma, mental stress, side efects of medicines, viral infections, and diet [9][10][11][12].Hence, as a symptomatic treatment, OU therapy aims to relieve pain, promote ulcer healing, and extend the intermittent period of recurrence.Te most commonly used medicines include glucocorticoids, growth factors, analgesics, anti-infammatory drugs, mouth rinses containing active enzymes, and vitamins [13].Unfortunately, the management of OU is still quite challenging with the undetermined efcacy of ulcer treatment.Brocklehurst found that no single therapy was efective enough for systemic intervention in OU [14].At the same time, some treatment medicines also bring quite a few adverse reactions that are unbearable for patients, for example, long-term use of glucocorticoids may cause oral mucosal atrophy and immunity defciency [15].Terefore, it is necessary to develop new therapies with higher efciency and lower side efects.
Acupuncture, a clinical subject that treats disease by stimulating acupoints on the body, is an important part of traditional Chinese medicine that runs thousands of years in East Asian countries.Meantime, as a complementary and alternative therapy, acupuncture has gained popularity in Western communities and the world at large.Te 2007 National Health Interview Survey demonstrated that over 14 million Americans have used acupuncture as part of their health care, which was an increase from 8 million in 2002 [16].Te rise indicates that more individuals are accepting acupuncture treatment as part of their current health-care regimen.Acupuncture reduces pain by activating specifc areas called acupoints on the patient's body.When these acupoints are fully activated, sensations of soreness, numbness, fullness, or heaviness called De qi or Te qi are felt by clinicians and patients [17,18].Recent studies have revealed that acupuncture can exert anti-infammatory and analgesic efects by regulating peripheral (involving local acupoints and infamed regions) and central neuroimmune interactions [19].Due to aforementioned merits, acupuncture has been used successfully to treat migraine, knee and back pain, chemo-induced nausea, vomiting, and hot fash among other disorders [20].In addition, acupuncture is often used to treat OU by relieving the pain of ulcer.Despite the numerous clinical research studies on acupuncture for OU, Wang et al. [21] showed that acupuncture can promote ulcer healing in patients with OU.Ren [22] believed that acupuncture can relieve the pain of OU.Liu [23] found that acupuncture can reduce the recurrence rate.Taking these inconsistent clinical outcome reports into account, a systematic evaluation is needed to summarize them to reach a consistent conclusion.Terefore, the aim of this systematic review and meta-analysis is to determine the efectiveness of acupuncture treatment for OU.

Methods
Tis system review had been registered on PROSPERO and the registration number was CRD42020144911.
2.1.Literature Search.Two researchers (Tianxi Chen and Yuqi Lin) conducted a comprehensive independent search on 8 electronic databases, including four English databases and four Chinese databases inceptions to December 2021.Four English databases including the Web of Science (WOS), PubMed, the Cochrane Library, and Embase; four Chinese databases including Chinese Biomedical Literature Database (CBM), Wanfang (WF), China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI).Te search terms were ("acupuncture") AND ("mouth ulcer" OR "oral ulcer" OR "recurrent aphthous stomatitis") AND ("randomized controlled trial").Te search strategy for PubMed is shown in Table 1.

Types of Study.
Te studies of acupuncture in the treatment of OU and the included studies were all randomized controlled trials (RCTs).Tere were no language or publication type restrictions.Quasi-RCTs and cluster RCTs were excluded.

Types of Participants.
Te inclusion criteria for participants were as follows: (I) participants who meet the diagnostic criteria of OU, regardless of their age, race, and gender.Te exclusion criteria of participants were as follows: (I) participants who meet Behcet's disease, Reiter's syndrome, recurrent erythema multiforme, or any viral infection; (II) participants who are not suitable for acupuncture treatment, such as pregnant or lactating women and patients with other serious medical conditions.

Types of Interventions.
Patients in the treatment group received conventional acupuncture, electroacupuncture, fre acupuncture, plum blossom acupuncture, press acupuncture, and other acupuncture therapies.Tere was no limit to the duration and frequency of treatment.

Types of Outcome
Measures.Te primary outcome measures assessed included the efective rate and the recurrence rate.Secondary outcome measures assessed included the visual analogue score (VAS) and the ulcer healing time.

Te Risk of Bias Assessment.
Te risk of bias assessment of all studies in this review was independently assessed by two evaluators (Yang Tu and Huangping Ai) using RoB 2.0 tool published by the Cochrane Handbook.Te following fve items were assessed: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result.According to the RoB 2.0 guide, the signal problem of multiple module settings was judged.Te signal problem answer was yes (Y), probably yes (PY), probably no (PN), no (no, N), or no information (NI).According to the signal answers given to diferent sections, the bias risk of each section was divided into low risk, some concerns, high risk, and the overall bias risk was given.If disagreement was seen in the assessments, this was resolved through discussion with a third researcher (Hang Yan).

Statistical Analysis.
We conducted the meta-analysis using RevMan5.3 and Stata16.0 software.Te odds ratio (OR) was used for dichotomous variables, mean diference 2 Evidence-Based Complementary and Alternative Medicine (MD) and 95% confdence interval (CI) were used for continuous variables.We tested heterogeneity using the I square (I 2 ) and P value (P).P < 0.1 or I 2 > 50% was considered to indicate signifcant heterogeneity and was calculated using a random-efects model.Otherwise (P ≥ 0.1 or I 2 ≤ 50%), the fxed-efect model was used, and the sources of heterogeneity were explored using subgroup analysis or sensitivity analysis.
2.8.GRADE Quality of Evidence Assessment.We used the GRADE profler software to rank the quality of the evidence for the outcome indicators.GRADE identifed fve factors that may reduce the quality of evidence in interventional systematic reviews: risk of bias, inconsistency, imprecision, indirectness, and other considerations.Te above fve factors were evaluated by GRADE pro software, and the quality of evidence was divided into the following four levels: high, moderate, low, and very low, and the levels represented the strength of the evidence.[24][25][26][27][28][29][30][31][32]; ② acupuncture plus Western medicine versus Western medicine (n � 4) [33][34][35][36]; ③ acupuncture plus Chinese medicine versus Chinese medicine (n � 5) [37][38][39][40][41]. Study characteristics of the included literature were summarized and listed in Table 2.

Risk of Bias in Included
Studies.Analysis of the included research trials according to ROB2 tool, 2 studies [24,26] were assessed as high risk in domain 1 because they used random methods with a higher risk of bias. 2 studies [35,37] were evaluated as low risk in domain 2 owing to mention blinding of participants.All included randomized controlled trials had low risk in domain 3 and domain 5.In terms of the overall risk of bias of the included studies, 2 studies [24,26] were high risk and 16 [25,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] studies were some concerns.Te risk of the bias table is shown in Figures 2 and 3.

Analysis of the Ulcer Recurrence Rate.
Six studies [24, 28-30, 33, 37] reported the recurrence rate involving a total of 506 cases in Figure 5. Subgroup analysis showed that acupuncture can reduce the recurrence rate of OU regardless of its subtypes.After combining efect size, the OR value was 0.24 (95% CI: 0.17 to 0.35, P < 0.01, I 2 � 0%).Four studies [24,[28][29][30] compared acupuncture with Western medicine, and the OR value was 0.21 (95% CI: 0.13 to 0.33, P < 0.01, I 2 � 16%); it indicated that the recurrence rate of the acupuncture group was lower than that of the Western medicine group.One study [33] compared acupuncture plus Western medicine with Western medicine, and the OR value was 0.30 (95% CI: 0.15 to 0.57, P < 0.01); One study [37] compared acupuncture plus Chinese medicine with Chinese medicine, and the OR value was 0.40 (95% CI: 0.09 to 1.70, P � 0.21).

Analysis of the Visual Analogue Score (VAS).
Five studies [25,30,34,37,41] reported the VAS indicator, involving a total of 382 cases in Figure 6.After combining efect size, the MD value was −1.79 scores (95% CI: −2.25 to −1.33, P < 0.01, I 2 � 86%).Two studies [25,30] showed that the visual analogue score in the acupuncture group was reduced by 2.26 scores compared with the Western medicine group   one study [34] was acupuncture plus Western medicine compared with Western medicine, and the MD was −1.44 scores (95% CI: −1.64 to−1.24,P < 0.01); two studies [37,41] showed that the visual analogue score in the acupuncture plus Chinese medicine group was reduced by 1.85 scores compared with the Chinese medicine group (MD � −1.85, 95% CI: −2.51 to−1.19,P < 0.01, I 2 � 52%).After sensitivity analysis, it was found that one study [25] was the main source of heterogeneity.Te heterogeneity was reduced after the removal of the study (I 2 � 72%, P < 0.01).

Publication Bias Assessment
3.8.1.Efective Rate Publication Bias.We used the Egger test to examine efective rate whether there was publication bias.In the acupuncture versus western medicine group, the result showed P � 0.018 (P < 0.05), indicating that the 9 included articles had publication bias.In the acupuncture plus Western medicine versus Western medicine group, the outcomes showed P � 0.643 (P > 0.05), meaning that there was no publication bias in the four included literature.In the acupuncture plus Chinese medicine versus Chinese medicine group, the results showed P � 0.372 (P > 0.05), demonstrating that the four included literature did not have publications bias.It was shown in Figures 8-10.

Recurrence Rate Publication Bias.
Publication bias analysis was performed on the recurrence rate and the results showed that P � 0.930 (P > 0.05), indicating that there was no publication bias in the acupuncture versus Western medicine group in Figure 11.[3.56, 7.11] Heterogeneity: chi 2 = 12.72, df = 16 (P = 0.69); I 2 = 0% Test for overall efect: Z = 9.17 (P < 0.00001) Test for subgroup diferences: chi 2  Evidence-Based Complementary and Alternative Medicine and healing time.Te results showed that the efective rate and recurrence rate were low quality, the VAS and healing time were very low quality.Te details are in Table 3.

Summary of the Results.
To the best of our knowledge, we expanded the scope of our search and found that there was still no signifcant evidence to support the efectiveness of acupuncture for OU in previous studies.Terefore, our study was the frst systematic review and meta-analysis to evaluate the efcacy of acupuncture on the treatment of OU.Tis study adopted the Chinese Stomatological Association's trial criteria for evaluating the efcacy of oral ulcer [42].Te specifc contents are as follows: the shortening of the average ulcer period and the pain index are markedly efective, the shortening of the average ulcer period or the pain index is efective, and the average ulcer period and the pain index which are not changed is invalid.We refer to the relevant content in the Guidelines for Clinical Research on New Chinese Medicines [43] that the recurrence rate of oral ulcer is three months after the end of treatment.Te results of this study summarized the existing evidence on the efcacy of acupuncture in patients with oral ulcer till December 2021.We searched 8 Chinese and English databases, 18 RCTs with 1422 participants were reviewed in the meta-analysis.Compared with the Western medicine group, the acupuncture group can improve the efective rate (OR � 5.40, 95% CI: 3.40 to 8.58), reduce the ulcer recurrence rate (OR � 0.21, 95% CI: 0.13 to 0.33), and relieve the ulcer pain (MD � −2.26, 95% CI: −4.27 to −0.24).Compared with the Western medicine group, the acupuncture plus Western medicine group can increase the efective rate (OR � 2.95, 95% CI: 1.48 to 5.85).Compared with the Chinese medicine group, the acupuncture plus Chinese medicine group can improve the efective rate (OR � 8.26, 95% CI: 3.61 to 18.88), relieve the ulcer pain (MD � −1.85, 95% CI: −2.51 to −1.19).Te above shows that the patients of OU could beneft from acupuncture therapy in terms of efective rate, ulcer recurrence rate, and visual analogue score.However, we performed the Egger test on the recurrence rate and efective rate.Te results indicated that there was publication bias in the efective rate in the acupuncture versus Western medicine group.Meanwhile, the grade evidence results demonstrated that the efective rate and recurrence rate were low, the VAS score and healing time were very low.Tis suggested that we should be cautious in applying these results in clinical practice.

Limitations of the Results.
Tere were some limitations of this research.First, the included 18 studies had methodological faws and were assessed as being of low quality.We speculated for the following reasons.In the included literature, only two studies mentioned blinding of     Evidence-Based Complementary and Alternative Medicine participants, and other studies did not clearly address randomization protocols, blinding methods, and allocation concealment, which may lead to selection, performance, and detection biases.Second, there was signifcant heterogeneity in the VAS and ulcer healing time as secondary outcome measures.We considered that both of these measures were subjective and easily infuenced by the experience of clinicians and reviewers.Simultaneously, the number of clinical studies was less in two outcome measures.Tere were only fve studies in the outcome measure of the VAS and four studies in the outcome measure of ulcer healing time, some results still need further confrmation.Tird, we considered publication bias in the article.We used Egger's test to detect the efective rate and found that there was publication bias in the acupuncture versus Western medicine group.Te specifc reasons need to be further analyzed.Above all, the operation of acupuncture was subjective and some treatment standards were difcult to be unifed.Tis study only focused on the stimulation method of acupuncture and did not analyze the diferences in acupuncture point selection, manipulation depth, and intervention time.Next, the literature search strategy only searched 4 English databases and 4 Chinese databases, grey literature was not taken into consideration.Ten, all the studies were published in China and there was potential publication bias in the included studies.Fourth, a subgroup analysis of ulcer classifcation would be more relevant in clinical practice, we did not perform a subgroup analysis of oral ulcer classifcation due to a small number of cases and incomplete data.

Suggestions for Future Studies.
Based on the currently published evidence, this meta-analysis study shows that acupuncture is efective in the treatment of oral ulcer.However, some of the included studies have methodological faws, which afect the authenticity, reproducibility, and comparability of research conclusions.It is not yet certain that acupuncture is completely superior to other treatments for oral ulcer.Terefore, we should formulate strict case inclusion and exclusion criteria and unifed efcacy evaluation criteria, which have good feasibility.At the same time, the classifcation of ulcers has important implications for treatment options, and a subgroup analysis of ulcer classifcation is needed to clarify the efcacy of acupuncture on   Evidence-Based Complementary and Alternative Medicine diferent ulcer subtypes in the future.Besides, specifc acupuncture points, acupuncture stimulation methods, needle insertion depth, needle response, treatment course, qualifcations of acupuncturists, assessors, and clinical practice years provide a rigorous, standard, and feasible treatment plan.Moreover, future still need more high-quality, multicenter, large sample, randomized, double-blind, and placebo-controlled trials to improve the quality of the methodology and reporting.

Conclusion
In conclusion, the results of this systematic review suggest that acupuncture may be more efective than Western medicine in terms of efcacy rate, and acupuncture combined with Western or Chinese medicine may have potential to reduce the recurrence of ulcer and relieve the ulcer pain.However, due to limited evidence, higher quality and more rigorously designed clinical trials with larger sample sizes will be needed to further confrm our fndings.

FullFigure 1 :
Figure 1: Flowchart of study selection process and screening results.

4
Evidence-Based Complementary and Alternative Medicine

Figure 2 :
Figure 2: Graph of the risk of bias: percentage of all studies included.

Figure 4 :
Figure 4: Forest plots of clinical efcacy rate in the three groups.

Figure 5 :
Figure 5: Forest plots of recurrence rate in the three groups.

Figure 6 :
Figure 6: Forest plots of visual analogue score (VAS) in the three groups.

Figure 7 :
Figure 7: Forest plots of healing time in the three groups.
a) Some study randomization methods, concealment, and blinding are not described.(b) Fewer included articles and observers.(c) Heterogeneity is signifcantly higher.(d) Publication bias.

Table 1 :
Te detailed search strategy in PUBMED as an example.
#12 AND # 31 AND# 40Evidence-Based Complementary and Alternative Medicine medicine with Western medicine, and the OR value was 2.95 (95% CI: 1.48 to 5.85, P < 0.01, I 2 � 0%); it indicated that the efective rate of acupuncture plus Western medicine group was higher than that of the simple Western medicine group.

Table 2 :
Characteristics and details of interventions of included studies.Chinese medicine, D: day, M: month, Y: year, ER: efective rate, RR:r ecurrence rate, VAS: visual analogue score, and UHT: ulcer healing time.

Table 3 :
GRADE evidence quality of outcomes included in the literature.