Is Acupuncture Another Good Choice for Physicians in the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome? Review of the Latest Literature

This study aimed to evaluate the efficacy and safety of acupuncture for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). A search of PUBMED, EMBASE, Central Register of Controlled Trials (CENTRAL), Web of Science, Chinese Biomedicine Literature (CBM), China National Knowledge Infrastructure (CNKI), Wang-Fang Database, Chinese Scientific Journal Database (VIP), and other available resources was made for studies (up to February 2019). Searches were limited to studies published in English and Chinese. Only randomized controlled trials (RCTs) related to the efficacy and/or safety of acupuncture for CP/CPPS were included. Two investigators independently evaluated the quality of the studies. A total of 11 studies were included, involving 748 participants. The results revealed that compared with sham acupuncture (MD: −6.53 [95% CI: −8.08 to −4.97]) and medication (MD: −4.72 [95% CI: −7.87 to −1.56]), acupuncture could lower total NIH-CPSI score more effectively. However, there are no significant differences between acupuncture and sham acupuncture in terms of IPSS score. In terms of NIH-CPSI voiding domain subscore, no significant differences were found between acupuncture and medication. Compared with sham acupuncture (OR: 0.12 [95% CI: 0.04 to 0.40) and medication (OR: 3.71 [95% CI: 1.83 to 7.55]), the results showed favorable effects of acupuncture in improving the response rate. Acupuncture plus medication is better than the same medication in improving NIH-CPSI total score and NIH-CPSI pain domain subscore. In conclusion, the evidence suggests that acupuncture may be an effective intervention for patients with CP/CPPS. However, due to the heterogeneity of the methods and high risk of bias, we cannot draw definitive conclusions about the entity of the acupuncture's effect on alleviating the symptoms of CP/CPPS. The adverse events of acupuncture are mild and rare.


Introduction
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex clinical entity consisting of urogenital pain, lower urinary tract symptoms, and/or sexual dysfunction that lasts for at least 3 months in the past 6 months [1]. CP/CPPS exists in more than 90-95% of patients with prostatitis [2], and it is estimated to affect 2-15% of adult men [3][4][5][6]. e lifetime prevalence of CP/CPPS is about 2.2% to 8.2% [7], and its main clinical symptoms are summarized as UPOINT, including pathogen infection, neuromuscular factors, and intraprostatic ductal reflux [8]. So it is essential to find an appropriate treatment for CP/CPPS. At present, antibiotics, anti-inflammatory drugs, alphablockers, and neuromodulators are the most commonly used drugs in the treatment of CPPS. However, the use of antibiotics remains controversial because there are no isolated bacteria [9]. Antiobstructive drugs that reduce pain and alpha-blockers that improve outflow tract obstruction should be taken within a limited period of time to offset the side effects [10]. Hence, more and more attention has been paid to phytotherapy and physiotherapy with less adverse reactions and high acceptance of patients in recent years.
Acupuncture is a form of alternative medicine and a key component of traditional Chinese medicine (TCM). It is most often used to relieve pain, though it is also recommended by acupuncturists for a wide range of other conditions. Different methods are used during acupuncture such as manual manipulation, electrical stimulation, and heat. Another form of acupuncture is acupoint catgut embedding. Studies reported that acupuncture had the effect of anti-inflammatory, immune modulation and neuromodulation. In 2016, Liu et al. [11] conducted a systematic review that shows acupuncture is effective in the treatment of CP/CPPS. It can relieve pain symptoms, reduce National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scores, and improve the quality of life of patients with CP/CPPS. However, due to insufficient number of high-quality, well-designed, randomized controlled trials (RCTs), the effect of acupuncture on CP/ CPPS is limited [12]. In the past three years, some new RCTs have been published on CP/CPPS treating with acupuncture. erefore, a comprehensive and systematic evaluation should be carried out.

Materials and Methods
e style of reporting the findings in the manuscript was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement [13].

Search Methods.
A search of PUBMED, EMBASE, CENTRAL, Web of Science, CBM, CNKI, Wang-Fang Database, VIP, and other available resources was made for studies (up to February 2019) that compared the efficacy and safety of acupuncture with sham acupuncture or medication (such as alpha-adrenergic antagonist, antibiotics, or antiinflammatory drugs). e search terms related to acupuncture, chronic prostatitis, chronic pelvic pain syndrome, and randomized controlled trials. Searches were limited to studies published in English and Chinese (see Table 1 for PUBMED database search strategy).

Types of Studies.
Only RCTs related to the efficacy and/ or safety of acupuncture for CP/CPPS were included. Trials used in meta-analysis should include the descriptions of adequate randomization methods, qualification diagnosis, qualification results reporting, and statistical methods. e quality of studies was evaluated by professional assessors. Articles focused on mechanisms, expert experience, animal experiments, reviews, and those without full text were excluded.

Types of Participants.
Participants diagnosed with CP/ CPPS (category III as classified by the NIH) were included. CP/CPPS was defined as urogenital pain, lower urinary tract symptoms, and/or sexual dysfunction that lasts for at least 3 months in the past 6 months in the absence of any urinary tract infection. Participants with benign prostatic hypertrophy, acute bacterial prostatitis, prostate cancer, severe heart disease, hepatic and kidney dysfunction, severe mental disease, or other serious diseases were excluded.

Types of Intervention.
Acupuncture compared to western drugs, acupuncture with drugs compared to the same drugs, and acupuncture compared to sham acupuncture were included. In addition, for the purposes of this review, we focused on acupuncture that can be performed in primary care settings, including any type of penetrating acupuncture (i.e., acupuncture, electroacupuncture, warm acupuncture, abdominal acupuncture, auricular acupuncture, acupoint catgut embedding, etc.). Comparison of two different types of acupuncture, acupuncture injections and acupuncture combined/compared with Chinese herbal medicine or acupuncture as a supplement to the effectiveness of the above interventions was excluded.

Types of Outcome Measures.
Changes in the total NIH-CPSI score [14], NIH-CPSI subscales, International Prostate Symptom Score (IPSS), and global response rate after treatment were recorded. In addition, adverse events from interventions were also recorded.

Data Collection.
We extracted the information of characteristics of participants, types of treatments and control groups, outcome measures, adverse events, and the follow-up period, if available (see Tables 2 and 3). For the purpose of this review, we extracted the change score of means and standard deviation, and when the data in the test report is insufficient, we try to contact the author. We estimated data using the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions if no one responded [26].

Data Synthesis and Analysis.
e measurement scales used to evaluate therapeutic effects were the NIH-CPSI (three domains: pain, voiding, and QoL; scores 0-43) and the IPSS (two domains: voiding and storage, scores 0-35). e scores of the acupuncture and control groups at the end of the original study period were compared. Response rate was defined according to the definitions in the original studies.

Pain Research and Management
All analyses were performed by the Review Manager statistical software (version 5.3). e continuous outcomes were analyzed using mean difference (MD) as the summary statistic. e dichotomous outcomes were analyzed using odds ratios (ORs) as the summary statistic. X 2 statistical tests (Q statistics) and the I 2 test were used to test the heterogeneity between the trials. e parameters with mean value and 95% confidence interval were transformed into mean values with standard deviation for calculation of weighted mean difference. [27] was used to evaluate the risk of bias for the RCTs included. Two investigators (JL and LD) independently evaluated the quality of the studies. References of previous published meta-analysis that met the enrollment criteria were included for pooled analysis. When discrepancies occurred, a third investigator (JY) is consulted to reach a consensus.

Results
As shown in the flow chart of selection ( Figure 1), a total of 1261 studies were searched, but only 693 studies were included for evaluation after duplications were removed. After excluding abstracts irrelevant to the topic, the full texts of 186 studies were retrieved for evaluation. Studies with inappropriate interventions, participants with bacteria prostatitis, or other prostate diseases were excluded. Studies without clear diagnosis and available date were also excluded.

References
Acupuncture and acupoints Lee et al., 2008 [15] Needle acupuncture, 4 points; CV1 (GuanYuan), CV4 (Huiyin), SP6 (Saninjiao), SP9 (Yinlinquan) Lee and Lee, 2009 [16] Electroacupuncture  were rated as having unclear risk of bias in this domain. Six RCTs comparing acupuncture to medication did not provide sufficient blinding information [17, 19-21, 23, 24], and we believe that the limitations of this approach may affect the results. erefore, those 6 trials are considered to have a high risk of bias in blinding domain. Four trials provided a total NIH-CPSI score without subscores and no adverse events or dropoffs, we considered a high risk of incomplete data and selective outcome reporting [17][18][19]24]. One RCT of a small group size was rated as high risk in other biased domains [16]. One RCT only said the trial was random but did not explain the random method; the trial was rated as having unclear risk of bias in random sequence generation domain [24] (Figure 2).

Discussion
is study is a systematic review and meta-analysis of the therapeutic effect of acupuncture on patients with CP/ CPPS. To investigate the efficacy of acupuncture, we combined the experimental data to calculate the mean difference by comparing the baseline and endpoint results of the control group. e results show that acupuncture is superior to sham acupuncture in terms of NIH-CPSI total score (MD: − 6.53 [95% CI: − 8.08 to − 4.97], P < 0.05), NIH-  [28,29], which demonstrated that acupuncture can improve IPSS better than sham acupuncture. e contradiction of sources is difficult to determine because subgroup analysis and sensitivity analysis are not possible without the availability of additional information from other trials. Compared to medication, the pooled results reveal that acupuncture is superior to this standard drug therapy as regards NIH-CPSI total score (MD: ere are different theories regarding the aetiology and pathophysiology of CP/CPPS, including infection [30][31][32], inflammation/autoimmunity [33], neuropsychological factors [34,35], adrenal axis abnormalities [36], pelvic floor muscles dysfunction [37,38], pelvic nerve entrapment [38], genetic predisposition to inflammation [39] and oxidative stress [40]. Due to the diversity of aetiology and pathophysiology of CPPS, standard drug treatment is unsatisfactory. e efficacy of antibiotics, alpha-blockers, and antiinflammatory drugs has been reported to be variable and frustrating. NIH-funded studies show that the efficacy of drug treatment for CPPS is negative [41,42]. Phytotherapy, such as low-energy shock wave, has also been reported in recent years for pelvic floor diseases, such as CP/CPPS [43] and erectile dysfunction [44]. erefore, many alternative therapies have been proposed, including phytotherapy, lifestyle changes, physical therapy, diet, cognitive behavioral therapy, and acupuncture [45].
Acupuncture, which is one of the most commonly used nondrug therapies, has been used to treat symptoms of CP/ CPPS patients in many countries. According to a report published by the World Health Organization [46], acupuncture has been widely used in various physiological diseases, including pain, infection, nervous system diseases, and urogenital diseases. However, the mechanism of the role of acupuncture is still unclear. At present, acupuncture is regarded as sensory nerve stimulus [47,48]. It has been used to relieve pain based on evidence of biological mechanisms and has been widely used in chronic diseases such as myofascial pain, muscle diseases, and neurological diseases in eastern countries [49].
e analgesic effect of acupuncture on CP/CPPS may involve levels of events on the tissue, spinal cord, and supraspinal, including regulation of the endogenous opioid system, gate control therapy, and the purinergic signaling system. In addition, increasing the levels of endomorphin-1, betaendorphin, encephalin, and serotonin may also be involved [50]. Acupuncture may also improve CP/CPPS symptoms by modulating the activity of immune cells and the secretion of immune molecules. Lee et al. [51] showed that acupuncture could increase the ratio of CD3+, CD4+, CD8+, CD19+, and NK cells, indicating that acupuncture can alleviate symptoms by modulating the immune system of CP/CPPS.
In this study, 5 trials did not provide information related to ADs [17-19, 23, 24]. Two trials reported no ADs [21,22]. Hematoma and pain at the needle site were reported in both the acupuncture and sham acupuncture groups in Lee 2008's finding [15]. Lower back pain near the needling was reported in sham electroacupuncture group in Lee 2009's study [16]. Qin, in 2018, revealed that hematoma occurred in 3 participants and 1 participant described sharp needling pain in acupuncture group; fatigue occurred in 1 participant in sham acupuncture group [25]. Zhao and Sun 2014 reported that 1 participant fainted during acupuncture treatment and 1 participant had hypotension after taking Tamsulosin [20]. Most studies reported little side effects associated with acupuncture. Acupuncture is, hence, a safe treatment for CPPS. Unskillful with acupuncture is an important factor in the occurrence of acupuncture side effects. is article has several limitations. First, all trials lack details of concealment, and most of them do not provide enough information about blind methods. Due to the characteristics of acupuncture, it is difficult for patients to be treated blindly, especially in case of using drugs in the control group. Second, the reaction time of acupuncture may be problematic because most studies have short-term followup, and there is very little data on the effects of repeated acupuncture. ird, there are still few high-quality studies comparing acupuncture with standard drug therapy. e small sample size of the study included may lead to publication bias. Fourth, different types of acupuncture, frequency of treatment, duration, and location of each course of treatment may have a potential impact on acupuncture. Due to insufficient trials, subgroup analysis or metaregression is difficult to avoid the limitations of this methodology. At last, this study did not determine which patients might benefit from acupuncture and which stimuli (pure needle, electrical, or catgut embedding) performed better. Although the current meta-analysis shows encouraging results, further research is necessary to determine what kinds of patients could benefit from acupuncture. Pain Research and Management 11

Conclusion
Acupuncture may be an effective intervention for patients with CP/CPPS. Compared with sham acupuncture, real acupuncture yielded a significant reduction in the NIH-CPSI score. Compared with medication, acupuncture is better in improving NIH-CPSI total score, pain domain subscore, and quality of life domain subscore. In addition, acupuncture plus medication is better than the same medication in improving NIH-CPSI total score and NIH-CPSI pain domain subscore. However, due to the heterogeneity of the methods and high risk of bias, we cannot draw definitive conclusions about the entity of the acupuncture's effect on alleviating the symptoms of CP/CPPS. e adverse events of acupuncture are mainly hematoma and local pain, which could be quickly relieved, and no other serious side effects were found.

Conflicts of Interest
e authors declare that they have no conflicts of interest regarding this work.