Acupuncture for Chronic Prostatitis or Chronic Pelvic Pain Syndrome: An Updated Systematic Review and Meta-Analysis

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex male dysfunction, mostly seen in young and middle-aged men with a history of more than 3 months. As a traditional therapy of Traditional Chinese Medicine, acupuncture has been proven an effective method to treat CP/CPPS in recent years. Though some meta-analyses on acupuncture for chronic prostatitis were published in 2018 and 2019, most of the included studies were low in quality according to the JADAD score (JADAD < 4). The conclusions of acupuncture for CP/CPPS remain indefinite. Purpose This review aims to evaluate the efficacy of acupuncture for CP/CPPS by including high-quality literature only (JADAD ≥ 4) to provide a reliable basis for clinical applications and research. Method Nine electronic databases were searched from inception to March 1, 2022, and only randomized controlled trials (RCT) with high-quality (JADAD ≥ 4) were included. Data were analyzed using Review Manager 5.3. and was verified through trial sequential analysis (TSA). We carried out a sensitivity analysis for the heterogeneity (I2 ≥ 50%). Publication bias was explored using a funnel plot. Result Ten RCTs (11 trials) of high-quality methodology involving 798 patients were included. Meta-analysis showed that compared to sham acupuncture (SAT) and western medicine (WM), acupuncture (AT) played superior roles for CP/CPPS patients in pain score, NIH-CPSI score, quality of life score, urinary symptom, and efficacy rate. As for the adverse effects, 4 RCTs described mild hematoma and pain in AT and SAT groups, while specific symptoms including nausea, abdominal pain, dizziness, and low blood pressure were reported in WM groups. Conclusion This meta-analysis indicated that acupuncture has measurable benefits on CP/CPPS, and security has also been ensured. However, this meta-analysis only included 10 RCTs; thus, RCTs with a larger sample size and longer-term observation are required to verify the effectiveness of acupuncture further in the future.


Introduction
Chronic prostatitis/chronic pelvic pain syndrome (CP/ CPPS) is a complex neurological dysfunction, and the incidence is on the rise year by year. According to foreign reports, the incidence of prostatitis is about 9%, and the recurrence rate is 20%-50% [1]. In China, epidemiologic studies have shown that the incidence of CP/CPPS is higher than in other countries, about 6.0% to 32.9% [2][3][4]. Patients with CP/CPPS usually sufer from varying degrees of pelvic pain or discomfort, and lower urinary tract symptoms and most prominent in the elderly [5]. It has ranked fourth among the 20 principal diagnostic diseases in the United States [6] and the third most commonly found urinary tract disease in men [7]. Men with chronic prostatitis have low blood fow in the common iliac vein, suggesting that pelvic congestion may be related to this condition [8]. Te urinary tract is naturally colonized with a specifc microbiome, and any imbalance may cause impairment and functional disorders [9]. Patients with CP/CPPS often experience urinary symptoms in their flling phase, urethral pain in the voiding phase, and recurrent urinary tract infections, which severely impact the patients' quality of life. Further, evidence supports a correlation between male infertility and prostatitis, as the prostate gland is the primary male accessory gland for male fertility. Many cases are underdiagnosed and undertreated by physicians [10].
Typical therapies such as alpha-blockers, antibiotics, and anti-infammatory medications occur with relatively modest efects on physiological functions; acupuncture may be an important consideration in difcult-to-treat pain syndromes. As a nonpharmacological intervention, acupuncture is a comprehensive concept of physical therapy that involves all kinds of needling techniques, moxibustion, and acupoint stimulation therapies. Researchers have confrmed that acupuncture is efective for CP/CPPS; however, most of the publications were nonrandomized studies [11][12][13][14][15][16]. Besides, though three similar SRs regarding acupuncture for CP/CPPS were published in 2018 [17], 2019 [18],and 2020 [19], according to the JADAD score, most of the included studies were low in quality. Furthermore, several relative trials [20][21][22] were conducted after the retrieval deadline (up to February, 2019) in 2020. Terefore, it is necessary to update a new SR by setting restricted inclusion and exclusion criteria and expanding search felds to draw a defnite conclusion about acupuncture for CP/CPPS.

Search Strategy.
Tis review was reported in conformity with the Preferred Reporting Item for Systematic Review and Meta-Analyses Statement. We searched PubMed, EMBASE, Springer, ICTRP, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Technology Periodical Database (VIP), Wan Fang Data, and China Biology Medicine (CBM) from the earliest available date until September 15, 2022. Te following keywords were used: acupuncture (AT), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and randomized controlled trial (RCT). Te language was restricted to Chinese and English. Study screening was performed independently by two researchers (Juanhong Pan and Di Zhang). Detailed search strategies based on guidance from the Cochrane handbook for PubMed, the Cochrane Library, and China National Knowledge Infrastructure (CNKI) would employ similar strategies for the other databases.

Quality of Studies.
Te methodological quality was assessed using an improved JADAD scale (0-3: low quality; 4-7: high-quality), and only articles with high-quality (JADAD ≥ 4) were included. Risk of bias was also performed by two reviewers (J.H.P. and D.Z.) following the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.3. Te items included random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Te quality of all the included trials was categorized as low/ unclear/high risk of bias ("Yes" for a low risk of bias, "No" for a high risk of bias, and "Unclear" otherwise). We evaluated every study and made judgments about potential bias.

Inclusion/Exclusion
Criteria. Te inclusion/exclusion criteria are available in the published protocols [23]. After we reviewed relevant articles, eligibility criteria for this review based on PICOS frameworks (population, intervention, comparison, outcome, and study) were as follows: (1) participants sufered from CP/CPPS; (2) broad acupuncture including traditional acupuncture (manual acupuncture, electronic acupuncture, dry needle, and scalp acupuncture) and acupuncture combination therapies (acupuncture combined with western medicine (it is medication, for example, tamsulosin capsule, levofoxacin hydrochloride or azithromycin capsules, and acupoint injection) seemed as experimental groups; (3) non -acupuncture was applied to control groups; (4) RCTs; (5) JADAD ≥ 4; and (6) study published in English or Chinese. Diferences in sex, age, country, time, and race were not taken into account. Studies were excluded if they were nonrandomized studies or used other forms of acupuncture, such as transcutaneous electrical nerve stimulation and laser acupuncture. Grey literature databases and websites were not searched. Tere were no restrictions on population characteristics and publication type.

Data Extraction.
Two authors (J.H.P. and D. Z.) screened the studies and collected the data independently according to the inclusion and exclusion criteria. Te information of author, publication year, country (language), demographics of participants, intervention, positive or negative conclusion, treatment duration (number), treating time, frequency (per week), time (per day), follow-up, outcomes, and JADAD score were recorded. All studies were managed with Endnote X9. Disagreements were resolved by discussion or umpired with a third reviewer (Y. W.).

Data Synthesis.
We developed inclusion/exclusion criteria for screening articles, followed by data extraction and quality evaluation. We used Review Manager 5.3 software provided by the Cochrane Collaboration for data analyses and presented the fnal result. For the continuous data, the mean diferences (MD) and 95% confdence intervals (CI) were used when outcomes were assessed by the same scale. I 2 statistical tests were adopted to assess the heterogeneity among studies. A fxed-efect model was applied to combine the data if the I 2 < 50%; otherwise, a random efect model was applied. If I 2 ≥ 50%, the heterogeneity was high, and sensitivity analysis would be considered. Te efcacy is dichotomous data and categorized into two levels ((1) efective and (2) inefcacious). Te efcacy rate means the percentage of the total number of participants categorized in the frst two levels. Publication bias was explored using a funnel plot.

Trial Sequential Analysis.
Meta-analysis usually requires multiple tests, and random errors may sometimes lead to false signifcant results when data are accumulated, and the increased frequency of statistical tests in a meta-analysis increases the possibility of reporting such results [24]. However, trial sequential analysis (TSA) overcomes the shortcomings of classical meta-analysis and corrects for the increase of type 1 error [25].
TSA.0.9.5.10 beta, was used for sequential analyses. If the Z-curve exceeds the traditional boundary but does not cross the TSA boundary, it suggests that a false positive error may be made. If it intersects the TSA boundary, it suggests that the meta-analysis results are robust, even if the RIS is not reached. Te Z curve did not intersect with the traditional cut-of value and the TSA cut-of value, and the positive or negative conclusion could not be drawn. Te Z-curve intersects the null line, indicating no signifcance [26]. We set a two-sided 5% type I error risk (α) and 20% type II error risk (β) to calculate the amount of information needed, with a 20% relative risk (RRR) reduction and a control event rate derived from data from the meta-analysis.

Study Selection.
A fow chart depicts the search process and study selection ( Figure 1). After primary searches from the databases, 2963 articles were screened. After reading the titles and abstracts, 2830 articles were excluded. Full texts of 133 articles were retrieved, and 123 articles were excluded with reasons listed as the following: not randomized (n � 18), no data for extraction (n � 5), low quality (n � 30), and others (n � 70). In the end, 10 RCTs were included. 5 were written by Chinese in Chinese [20,21,[27][28][29], 3 [22,30,31] of which were written by Chinese in English, 1 by Malaysian in English [32], and 1 by Turkish in English [33].

Study Characteristics.
Te characteristics of included RCTs are listed in Tables 1 and 2. A total of 798 patients with CP/CPPS were included. Tere were 11 trials that specifed 9 diagnostic criteria of CP/CPPS. Te age, frequency, and treatment duration varied from 18 to 55 years, 1 d/w to 3 d/ w, and 20 to 24 times a course, respectively. Te intervention of treatment groups included scalp acupuncture, acupoint injection, electric acupuncture, acupuncture, and Tiaoshen acupuncture. Te intervention of control groups included western medicine and sham acupuncture. Te outcomes were NIH-CPSI, pain, urinary symptoms, quality of life, and efcacy rate.

Publication Bias.
As can be seen in Figure 3, all studies were not outside the funnel plot, but publication bias could be suspected based on the funnel plot asymmetry. [20][21][22][27][28][29][30][31][32][33] reported the total clinical efective rate, which were analyzed sequentially, with a type I error of 5% and a statistical power of 80%. Te information axis was set as the cumulative sample size, and the sample size was used as the expected information value (RIS). Figure 4 [20,21,28,29]shows that the Z-curve crosses the conventional boundary value and the TSA boundary value, indicating that the results obtained from this meta-analysis are robust and the efcacy of acupuncture in the treatment of CP and CPPS is positive. Meantime, the penalty curve also exceeded the traditional boundary value, which made the meta-analysis result more stable, but it did not reach the RIS value, and further research is needed.

Trial Sequential Analysis. Eleven RCTS
In Figure 5 [22,27,[30][31][32][33], although the Z curve crossed the traditional boundary value curve and the penalty curve crossed the traditional boundary value curve, the Z curve did not cross the TSA boundary value curve and did not reach the RIS value, indicating that the results of meta-analysis may have false positive, and further research is needed to further prove the efcacy of acupuncture and sham acupuncture in the treatment of CP and CPPS.

Efect of the Interventions.
Based on various outcome measures (pain score, urinary symptom, NIH-CPSI score, quality of life, and efcacy), diferent pooled data from 11 trials were used. Te data were divided into stratifed analyses according to diferent interventions of control groups. Te efect of acupuncture on CP/CPPS is shown below, respectively.

Discussion
Tere were 10 studies, including 1 three-arm trial, with 798 patients included in the total. Acupuncture, as one of the traditional Chinese medicine therapies, includes many diferent acupuncture methods. In this meta-analysis, standard acupuncture and moxibustion, electroacupuncture, Tiaoshen acupuncture, scalp acupuncture, acupuncture combined with western medicine, and acupoint injection were all classifed as broad acupuncture therapy  Pain Research and Management (AT). All of them have been evaluated and compared with western medicine and sham acupuncture. Te overall quality of these identifed trials was high (JADAD ≥ 4). Te overall trials were at low risk. All studies have reported random sequence generation and prespecifed expected outcomes without missing data. However, some studies were recorded defciently about the outcome of blinding of participants and outcome assessment, and meantime, it was hard to judge the existence of the important other bias due to the original data were not available.
Despite the methodological quality and risk of bias limitations, acupuncture (AT) displayed a superior efect in the improvement of pains, urinary symptom, quality of life, NIH-CPSI score, and efcacy than western medicine (WM) and sham acupuncture (SAT). We found that in the acupuncture versus western medicine group, the heterogeneity in NIH-CPSI decreased after excluding 1 study (I 2 � 8%, P < 0.00001) [28], of which the intervention was scalp acupuncture, while the others were manipulated by body acupuncture. Our fndings indicate that diferent acupuncture positions might be the sources of the heterogeneity. Besides, we found that there are no signifcant diferences in improving urinary symptom scores between the two groups (P � 0.06), which was contrary to the original study. We speculated this inconsistency might be related to the process of raw data for being failed to contact the author. As for the results of quality of life in the acupuncture versus sham acupuncture group, the heterogeneity decreased (I 2 � 17%, P < 0.00001) after eliminating 1 study [32]. According to Figures 2 and 7, the frequency of this study was 3 d/w, but other studies <3 d/w, which would be related to the high heterogeneity, and we speculated the frequency ≥3/w was more efective.
Meanwhile, to confrm the stability of the results of this meta-analysis, a trial sequential analysis was performed. Figure 4 [20,21,28,29] shows that the Z-curve crosses the conventional boundary value and TSA boundary value, although it does not reach the RIS value, indicating that the results obtained in this meta-analysis are robust. Compared with western medicine, the efcacy of acupuncture in the treatment of CP and CPPS is positive, and the penalty curve also exceeds the traditional boundary value, making the results of the meta-analysis more stable. In Figure 5, [22,27,[30][31][32][33], although the Z-curve crosses the traditional boundary value curve and the penalty curve crosses the traditional boundary value curve, the Z curve does not cross the TSA boundary value curve, indicating that there may be false positive results in the meta-analysis, and further research is needed to further prove the efcacy of acupuncture and sham acupuncture in the treatment of CP and CPPS. However, unfortunately, the Z-curve did not exceed the RIS value in both analyses, indicating that a lot of research is needed in this regard.
Because the etiology and pathophysiological mechanism of chronic prostatitis are still unclear, current reports suggest that the pathogenesis of CP/CPPS may be related to abnormal immune response [34], central sensitivity [35][36][37], oxidative stress [38], pelvic foor muscle spasm [39] and neuropsychology [40]. Currently, there is no clinically clear treatment for CP/CPPS. Te traditional main measures of Xia et al. 2020 [21] Tiaoshen acupuncture, 14    Pain Research and Management CP/CPPS include taking anti-infammatory drugs, antibiotics, and α receptor blockers, but long-term use will lead to adverse reactions such as nausea, dizziness, gastrointestinal discomfort, and hypotension [41], and some drugs even have no obvious therapeutic efect [42,43]. Terefore, patients turn to alternative therapies such as acupuncture and cognitive behavioral therapy, especially acupuncture, which has been recognized for its good efcacy and high acceptance.
Related studies have shown that acupuncture can signifcantly reduce the pain of CP/CPPS patients, improve the NIH-CPSI symptoms, and improve the quality of life in patients [44]; the reasons include the following three mechanisms: (1) acupuncture can reduce the expression levels of interleukin (IL-6, IL-8), tumor necrosis factor (TNF) -α, prostaglandin E2, interferon (IFN) -c and other infammatory factors [45][46][47][48][49][50][51][52]. Increasing the expression levels of anti-infammatory factors IL-2 and IL-10 and increasing the levels of CD3+, CD8+, and CD25+ in peripheral blood immune cells of CNP patients can regulate their immune function [53]. (2) Persistent chronic pain can reduce gray matter volume [36,54] and activation [55] in brain regions such as the anterior cingulate gyrus in CP patients. Te research on the central mechanism of acupuncture in the treatment of CP is still unclear, but there have been a large number of studies on the central analgesic efect of acupuncture [56]. For example, acupuncture can inhibit the formation of synaptic plasticity and afect the central sensitization state, and regulate the mitogenactivated protein activation (MAPK) mainly cell signaling pathway by inhibiting glial cell activation, and downregulate the expression of TRPV1, purine receptor (P2X3), and endocannabinoid receptor. Te central analgesic efect was comprehensively exerted [57]. (3) Te increase of oxidative stress products leads to the sensitization of nerve endings, which is an important factor in the occurrence of CP  8 Pain Research and Management [58,59]. Among them, the release of substance P and the inhibition of β-endorphin release make CP patients continue to have pain symptoms [60,61]. Acupuncture can reduce the release of substance P and inhibit the increase of β-endorphin secreted by immune cells, so as to alleviate the clinical symptoms of CP patients [62].
Tere are 4 studies [21,22,24,28] that described the adverse events. In acupuncture and sham acupuncture groups, specifc skin symptoms including mild subcutaneous bleeding and pain were reported, while in the western medicine groups, gastrointestinal symptoms including nausea, abdominal pain, dizziness, and low blood pressure were recorded. Compared to drugs, acupuncture was safer. Te security of acupuncture is ensured.
Tis review indicated that acupuncture is of signifcant beneft for CP/CPPS by setting strict inclusion/exclusion criteria and controlling the methodology quality. However, there were several limitations in this review. First, the methodological faw is blinding absence, including participant blinding, therapist blinding, and assessor blinding, and researchers should pay more attention to the use of blinding in the future. Second, the data were extracted from 10 high-quality studies (JADAD ≥ 4) ( Table 1), while most of them were with small samples (n < 50), and larger sample size high-quality studies are needed to confrm the efectiveness of acupuncture. Tird, it can be seen from feature Table 2  Because of the small number of included literature and no stratifcation, the choice of acupoint may have an impact on the results of meta-analysis. In the future, high-quality literatures can be accumulated for further exploration. Fourthly, in this meta-analysis, we did not analyze the effcacy of acupuncture and diferent drugs (such as tamsulosin capsules, levofoxacin hydrochloride, or azithromycin capsules) on CP/CPPS, and new meta-analyses can be

Conclusion
Tis meta-analysis indicated that acupuncture (AT) has measurable benefts on CP/CPPS (pain, urinary symptom, quality of life, NIH-CPSI score, and efcacy rate), and the security of acupuncture was also ensured. However, methodological faws, such as a small sample, the follow-up absence, and diferent kinds of acupuncture treatments exist,  thus RCTs with larger sample sizes and longer-term observation are required to verify the efectiveness of acupuncture further, and a new meta-analysis can be conducted to analyze the efcacy of diferent acupuncture treatments on CP/CPPS in the future.