DOI: https://doi.org/10.21203/rs.3.rs-2050378/v1
Background:
Chronic prostatitis (CP) is one of the most common diseases in urology. Longdanxiegan decoction (LDXGD), a classical formula of traditional Chinese medicine (TCM), has been widely used for chronic prostatitis patients with the damp invasion of lower energizer syndrome in China, and the effects were satisfactory. However, there is still no clear understanding of its clinical effects.
Purpose:
This study aimed to systematically evaluate the efficacy and safety of LDXGD for chronic prostatitis.
Methods:
Pubmed, EMBASE, Cochrane Library, China Biology Medicine disc (CBMdisc), China national knowledge infrastructure (CNKI), Wanfang, and VIP database were searched from their inceptions to August 11, 2022 to identify RCTs that inspected the efficacy of LDXGD on chronic prostatitis.
Results:
12 trials totaling 1314 patients were identified for analysis. Meta-analysis showed that LDXGD treatment was more effective (RR=1.31, 95%CI (1.18, 1.45), P<0.00001) and cure rate (RR=1.79, 95%CI (1.52,2.12), P<0.00001) than western medicine. Meanwhile, LDXGD had reduced NIH-CPS score, such as the total score, pain domain score, urinary domain score, and QoL domain score. Besides, LDXGD was more effective in improving EPS - WBC count. LDXGD safety remained unknown.
Conclusions:
According to preclinical evidence, LDXGD could be an effective and promising treatment for chronic prostatitis. In addition, more well-designed studies are needed to confirm this conclusion.
Trial registration: PROSPERO 2022 CRD42022347076.
Chronic prostatitis (CP) is a common urological disease characterized by pelvic pain, lower urinary tract symptoms (LUTS), psychosomatic symptoms and sexual dysfunction [1]. Epidemiological studies showed that the prevalence of CP ranges between 8.4 and 25% worldwide [2]. According to the National Institutes of Health (NIH) classification system, CP can be defined as Category II (Chronic bacterial prostatitis) and Category III (Chronic nonbacterial prostatitis/chronic pelvic pain syndrome) [4]. CP has complex pathogenic factors, which can be caused by infection, psychosomatic aspects, pelvic floor muscle dysfunction, and autoimmune factors [5]. Treatment of CP includes conventional therapies such as alpha-blockers, antibiotics, and anti-inflammatory drugs. Alpha-blockers are currently the typical drug for relieving lower urinary tract symptoms, improving urination and quality of life. Antibiotics are another medicine for treating chronic prostatitis with proven anti-inflammatory and pain reduction effects [6]. Still, the long-term use of antibiotics may have adverse effects on liver damage, intestinal reactions, crystalluria [7].
Traditional Chinese medicine has a long history of practice in the treatment of CP. CP is termed "stranguria" and "turbid Sperm" in Chinese medicine. The causes of the disease include excessive consumption of spicy food or alcohol, emotional disorders, uncleanliness of the lower yin, strain, and internal injury resulting in the accumulation of damp-heat in the lower energizer, the pathogenesis of damp-heat injection [8]. Longdanxiegan decoction (LDXGD) is a combination of 10 herbs, namely Longdancao (Radix Gentianae), Zhizi (Gardenia Jasminoide), Huangqin (Radix Scutellariae), Mutong (Caulis Akebiae), Cheqianzi (Semen Plantaginis), Zexie (Rhizoma Alismatis), Danggui (Radix Angelicae Sinensis), Shangdihuang (Radix Rehmanniae Glutinosae), Chaihu (Radix Bupleuri), Gancao (Radix Glycyrrhizae). Many diseases can be treated with LDXGD, including chronic prostatitis, chronic gastritis [9], psoriasis vulgaris [10], insomnia [11], hypertension [12], Eczema [13], etc.
Although there are many RCTs that discussed LDXGD in the treatment of chronic prostatitis, the research studies were fragmented and lacked incongruent. In addition, due to different sample sizes, dosages, outcome indicators, and nonuniformity of evaluation criteria study conclusions are inconsistent. Therefore, our study aims to comprehensively evaluate the efficacy and safety of LDXGD through the following procedures: (a) compare the efficacy of LDXGD alone used with western medicine. (b)compared the effectiveness of LDXGD plus western medicine with western medicine. (c)To examine the safety of LDXGD.
This systematic review and meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the register number is CRD42022347076[14].
Search Strategies
We systematically searched seven databases, including Pubmed, EMBASE, Cochrane Library, China Biology Medicine disc (CBMdisc), China national knowledge infrastructure (CNKI), Wanfang, VIP database from their inceptions to August 11, 2022 to identify RCTs that inspected the efficacy of LDXGD on chronic prostatitis. The following terms were used for searching: (“prostatitis” OR prostatism OR chronic prostatitis OR chronic pelvic pain syndrome OR abacterial prostatitis OR non-bacterial prostatitis OR prostatodynia) AND (“Longdan xiegan” OR “longdanxiegan” OR “long dan xie gan” OR “Longdanxiegan decoction” OR “Longdanxiegan tang” OR “Longdanxiegantang”) AND (“clinical trial” OR “randomized controlled trial” OR “randomized controlled trial). We manually searched for possible relevant studies and the language and publications in our search were not specified.
Inclusion Criteria
(1) Type of participants: the trial involved patients with prostatitis category 2 (chronic bacterial prostatitis) or category 3 (chronic pelvic pain syndrome).
(2) Type of study: only RCTs that evaluated the efficacy of LDXGD for the treatment of chronic prostatitis.
(3) Type of intervention: LDXGD was the active intervention in the experimental group. There was no limit on the drug dosage, frequency, or treatment time. The control group was treated with antibiotics or alpha1-blockers.
(4) Type of results: the primary outcome measure was clinical cure rate, total effective rate. Secondary outcomes included the NIH-CPSI total score, NIH-CPSI Pain Subscale, NIH-CPSI Urinary Subscale, NIH-CPSI QOL Subscale, EPS-WBC, and adverse events.
Exclusion Criteria
If the following conditions were identified, the study should be excluded:
(1) the studies were not randomized or did not have a control group
(2) the literature is not clear on the diagnosis of chronic prostatitis
(3) duplicate publications, animal experiments, studies, case reports, and reviews.
(4) not available full text of the literature.
(5) the control group contained LDXGD.
Study Selection
Firstly, two separate reviewers (HC and XW) independently searched the previously mentioned databases and listed the titles of all articles. According to the inclusion criteria, reading through the title and abstract, they excluded the studies that were not eligible. Secondly, the unclear articles were further screened. If there was divergence, they agreed through discussion, or a third evaluator (XS) was consulted. If the information was incomplete, further contact was made with the primary researcher of the literature to obtain any missing information.
Assessment of Literature Quality
Two separate reviewers (HC and XW) independently evaluated the risk of bias of these studies according to Cochran’s Systematic Review Handbook risk assessment tool [15]. It comprised the following 7 aspects: 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), other bias. The quality assessment results of each item were categorized as “low risk”, “high risk of bias” or “unclear risk”. When necessary, there was a discussion among the reviewers to resolve differences.
Data Synthesis and Analysis
Review manager 5.4 software was used for statistical analysis. The dichotomous outcomes were presented as relative risk (RR) and 95% confidence interval (CI). And for the continuous outcomes were described by mean difference (MD) between intervention and control groups with 95% confidence interval (CI). Heterogeneity was judged according to the results of I2 test. The fixed-effect model was used when I2<50%. Furthermore, the random effect model was used when I2>50%. Subgroup analysis was conducted by different treatment methods in the control group. When there were more than 10 included studies in the meta-analysis, inverted funnel plots determined publication bias.
Search Results.
Based on our search strategy in 7 electronic databases, 159 potentially relevant publications resulted. After removing the duplicates, 81 studies remained. By screening the titles and abstracts, 41 studies were excluded. After reading the full text, 12 eligible studies were included for meta-analysis [16-27]. The flow chart showing the process of literature retrieval and screening is shown in Figure 1.
Study Characteristics.
Table 1 summarizes the basic characteristics of the 12 RCTs. A total of 1314 patients with chronic prostatitis were included. All the trials were published in China. Sample sizes ranged from 60 to 252. The course of treatment ranged from 2 weeks to 3 months. In the experimental group, LDXGD alone was used in 6 trials, and LDXGD plus alpha-blockers were used in 3 trials, then LDXGD plus antibiotics (LCWA) was used in 1 trial, LCWA plus alpha-blockers was used in 2 trials. The components of LDXGD or modified LDXGD were listed in Table 2. In the control groups, antibiotics alone were used in 2 trials, then alpha-blockers alone were used in 5 trials, and antibiotics plus alpha-blockers were used in 7 trials. All included trials reported the efficacy of LDXGD in the treatment of chronic prostatitis. Clinical cure rate, total effective rate and NIH-CPSI total score were the primary outcomes. 10 trials reported clinical cure rate [16-17, 19, 21-27], and 12 trials reported total effective rate [16-27], then 6 trials reported NIH-CPSI total score [16-17, 19-20, 22, 24]. In terms of secondary outcome, 4 trials reported NIH-CPSI Pain Domain Score and NIH-CPSI Urinary Domain Score [17, 19, 23, 26], 2 trials reported NIH-CPSI QoL Domain Score [17, 19], 3 trials reported EPS - WBC [17, 21, 24] and only one trial reported adverse effects [17].
Methodological Quality
Although randomization was announced in all the included trials, 4 RCTs [17, 19, 23-24] used the method of a random number table. Accordingly, the risk of bias on the domain was judged as “low risk.” 4 RCTs [16, 18, 20, 25] had “high risk” cause the random sequence was generated based on the treatment method grouping or date of visit. The rest of the RCTs [21, 22, 26-27] only described “random” without a specific method and evaluated were as “unclear risk”. None of the studies mentioned allocation concealment or blinding of participants, and outcome assessment was considered "unclear risk." 11 RCTs recommended that the outcome data were complete and 1 RCT [24] indicated that have 1 participant dropped out in the control group. and all RCTs were assessed as “low risk.” According to baseline data, we assessed other biases, including gender, age, and duration, and all trials were judged as "low risk" (shown in Figures 2 and 3).
Outcomes
1. Clinical cure rate
10 trials reported the clinical cure rate [16-17, 19, 21-27]. The clinical cure rate was found to have low heterogeneity, the fixed-effects model was used. The meta-analysis evaluated that LDXGD was better at improving the clinical cure rate of chronic prostatitis (RR=1.79, 95%CI (1.52,2.12), P<0.00001, I2=0%, P=0.64). There was no significant difference between the LDXGD group and the antibiotics group (P=0.10). 5 trials compared LDXGD with antibiotics plus alpha-blockers, and there was a significant difference between them (RR=2.15, 95% CI (1.67, 2.76), P<0.00001, I2=0%, P=0.91). 2 trials compared LDXGD plus alpha-blockers with alpha-blockers, and there was a significant difference between them (RR=1.78, 95% CI (1.16, 2.74), P=0.009, I2=0%, P=0.45). And our meta-analysis revealed that the LCWA group compared antibiotics group and LCWA plus alpha-blockers compared with antibiotics plus alpha-blockers group were no statistically significant difference (shown in Figure 4).
2. Total effective rate
All studies reported the total effective rate [16-27]. Cause high heterogeneity was observed, the random-effects model was used. Meta-analysis showed that LDXGD was better at increasing the total effective rate of chronic prostatitis (RR=1.31, 95%CI (1.18, 1.45), P<0.00001, I2=72%, P<0.0001). one studies compared LDXGD group with antibiotics group, and there was a significant difference between them (RR=1.39, 95%CI (1.03, 1.88), P=0.03). 5 studies compared LDXGD used alone with antibiotics plus alpha-blockers and there was a significant difference between them (RR=1.4, 95% CI (1.1, 1.78), P<0.00001, I2=86%, P<0.00001). 3 studies compared LDXGD plus alpha-blockers with alpha-blockers, and there was a significant difference between them (RR=1.28, 95% CI (1.13, 1.45), P=0001, I2=0%, P=0.67). And 1 study compared LCWA with antibiotics, there was a significant difference between them (RR=1.12, 95% CI (1.01, 1.23), P=0.03). 2 studies compared LCWA play alpha-blockers with antibiotics plus alpha-blockers, there was a significant difference between them (RR=1.26, 95% CI (1.12, 1.43), P=0.0001, I2=0%, P=0.87) (shown in Figure 5).
3. NIH-CPSI- total score
The meta-analysis for the NIH-CPSI total score outcomes included 6 studies [16-17, 19-20, 22, 24]. Cause remarkable heterogeneity was observed, the random-effects model was used. 2 studies compared LDXGD groups with antibiotics plus alpha-blockers groups, there was a significant difference between them (MD=-2.15, 95% CI (-3.32, -0.97), P<0.0003, I2=41%, P=0.19). 2 studies were statistically significant difference when LDXGD plus alpha-blockers groups compared with alpha-blockers groups (MD=-3.52, 95% CI (-4.59, -2.45), P=0.29). 1 study compared the LCWA group compared with antibiotics groups, and there was a significant difference between them ((MD=--6.69, 95 %CI (-7.35, -6.03), P<0.00001). 1 study compared LCWA plus alpha-blockers group compared with the antibiotics plus alpha-blockers group, and there was a significant difference between them ((RR=-3.3, 95% CI (-4.33, -2.27), P<0.00001) (shown in Figure 6).
4. NIH-CPSI Pain Domain Score
In a meta-analysis of 4 studies [17, 19, 23, 26] reported the NIH-CPSI Pain Domain Score. Because remarkable heterogeneity was observed, the random-effects model was used. When LDXGD was compared with antibiotics plus alpha-blockers, the result showed that NIH-CPSI Pain Domain Score was lower (MD=-4.04, 95%CI (-4.6, -3.48), P<0.00001). There were statistically significant differences in LDXGD plus alpha-blockers groups compared to the alpha-blockers groups (MD=-2.53, 95%CI (-3.12, -1.94), P<0.00001). 1 study compared LCWA plus alpha-blockers group compared with antibiotics plus alpha-blockers group, and there was a significant difference between them (MD=-3.73, 95%CI (-4.13, -3.33), P<0.00001) (shown in Figure 7).
5. NIH-CPSI Urinary Domain Score
4 studies [17, 19, 23, 26] reported the NIH-CPSI Urinary Domain Score. The results of the heterogeneity test were P<0.00001 and I2=99%, it showed high heterogeneity, so the random effect model was used. 1 study compared LDXGD with antibiotics plus alpha-blockers, and there was a significant difference between them (MD= -5.93, 95% CI (-6.55, -5.31), P<0.00001). There was a statistically significant difference between the LDXGD plus alpha-blockers groups and alpha-blockers groups (MD= -1.86, 95% CI (-3.00, -0.72), P<0.00001). 1 study compared LCWA plus alpha-blockers group with the antibiotic plus alpha-blockers group, there was a significant difference between them (MD=-1.16, 95% CI (-1.58, -0.74), P<0.00001) (shown in Figure 8).
6. NIH-CPSI QoL Domain Score
2 studies [17, 19] reported the NIH-CPSI QoL Domain Score. The results of heterogeneity test were P=0.89 and I2=0%, it showed had a low heterogeneity, so the fixed effect model was used. There was a statistically significant difference between the LDXGD plus alpha-blockers groups and alpha-blockers groups (MD=-1.94, 95% CI (-2.4, -1.47), P<0.00001) (shown in Figure 9).
7. EPS - WBC count
3 studies [17, 21, 24] reported a count of EPS - WBC. The results of the heterogeneity test were P<0.00001 and I2=98%, it showed high heterogeneity, so the random effect model was used. The results showed that the count of EPS-WBC (MD=-9.88, 95%CI (-14.34, -5.42, I2=98%, P<0.0001)) after treatment of experimental groups was lower than in control groups, and the difference was statistically significant (shown in Figure 10).
8. Adverse events
Only 1 study reported adverse events. Han [17] reported the experimental group had 2 cases of dizziness, 1 case of totter. The frequency of adverse events in the experimental group was 3/45. On the other hand, the control group had 3 cases of dizziness, 2 cases of totter, 1 case of orthostatic hypotension, 1 case of gastrointestinal discomfort, and 1 case of abnormal liver function. The other studies did not report adverse events frequency. The frequency of adverse events in the control group was 8/45.
Publication Bias.
A funnel plot of the total effective rate was used to analyze publication bias. The results revealed that there was a publication bias in the included studies. We believe that the reason for the bias was the small size samples of these trials. LDXGD may have an overestimated effect on chronic prostatitis patients as a result of potential publication bias (shown in Figure 11).
In this meta-analysis, we included 12 trials and 1314 patients with chronic prostatitis, With the data, we measured the efficacy of LDXGD in the treatment of chronic prostatitis, including LDXGD vs. Antibiotics, LDXGD vs. Antibiotics plus alpha-blockers, LDXGD plus alpha-blockers vs. alpha-blockers, LCWA vs. Antibiotics, LCWA plus alpha-blockers vs. Antibiotics plus alpha-blockers.
The main finding of this study was that LDXGD either used alone or combined with antibiotics or alpha-blockers resulted in a statistically significant improvement in the total effective rate (RR=1.31, 95%CI (1.18, 1.45), P<0.00001) and the clinical cure rate (RR=1.79, 95%CI (1.52,2.12), P<0.00001). When used alone, LDXGD had significantly improved the total effective rate (RR=1.4, 95% CI (1.1, 1.78), P<0.00001) and the clinical cure rate (RR=2.15, 95% CI (1.67, 2.76), P<0.00001), compared with antibiotics and alpha-blockers groups. Our second finding was that LDXGD significantly reduce NIH-CPSI score. NIH-CPSI is commonly used for the assessment of symptom severity in men with chronic prostatitis/chronic pelvic pain syndrome. In this meta-analysis, LDXGD either used alone or combined with antibiotics or alpha-blockers resulted in a statistically significant reduction in the NIH-CPSI- total score (MD=-2.15, 95% CI (-3.32, -0.97), P<0.0003), NIH-CPSI Pain Domain Score (MD=-3.45, 95% CI (-4.26, -2.63), P<0.00001), NIH-CPSI Urinary Domain Score (MD=-2.7, 95% CI (-4.73, -0.66), P<0.00001), and NIH-CPSI QoL Domain Score (MD=-1.94, 95% CI (-2.42, -1.46), P<0.00001).
The third finding of this paper was that LDXGD either used alone or combined with antibiotics and alpha-blockers resulted in a statistically significant reduction in EPS-WBC count (MD=-9.88, 95% CI (-14.34, -5.42), P<0.0001). EPS-WBC count is often used as an important indicator to determine the presence or absence of prostatitis and to determine the severity of prostatitis. CP patients may benefit from LDXGD as a complementary and alternative treatment option, especially if they are intolerant to antibiotics and alpha-blockers.
Our meta-analysis revealed high heterogeneity in total effective rate (I2=72%), NIH-CPSI- total score(I2=95%), NIH-CPSI Pain Domain Score(I2=87%), NIH-CPSI Urinary Domain Score(I2=98%), and EPS - WBC count(I2=98%). The high heterogeneity could be attributed to several factors. Firstly, some studies used modified versions of LDXGD with added or deducted herbs. Secondly, sample sizes might be too small for certain studies, which could easily affect the outcome of this meta-analysis.
In the traditional Chinese medicine theory, damp-heat in the lower energizer syndrome is one of the most clinical syndromes. Its main symptoms include dripping and painful urination, muscle constriction in the lower abdomen, perineal swelling and pain, and cloudiness of urine. These symptoms are very similar to those of chronic prostatitis. LDXGD demonstrates its unique advantages in treating CP. From the perspective of traditional Chinese medicine theory, Longdancao can not only clean excessive heat of the liver-gallbladder but also clean damp heat in it. Huangqin and Zhizi clear heat and drain fire, Zexie, Mutong and Cheqianzi can dispel heat by excreting dampness, Danggui and Shengdihuang can nourish Yin and blood, Chaihu disperses the depressed liver energy, and Gancao can moderating the property of other herbs. Therefore, by purging heat and dampness of the liver and gallbladder, LDXGD makes a good traditional Chinese medicine formula for treating damp-heat in the lower energizer syndrome. Modern pharmacological research reveals that the pharmacological effects of LDXGD include the following: a) immunomodulatory effects: the immunomodulatory effects of LDXGD mainly include humoral immunomodulation and cellular immunomodulation. Zhang’s [28] experiments prove that LDXGD increased the serum lysozyme level, hemolysin antibody level and T-lymphocyte conversion rate in mice, and there was a quantitative-effect relationship that the effect increased with increasing dose. According to Zhang’s, LDXGD can relieve symptoms of anal sinusitis, regulate pro-inflammatory/anti-inflammatory balance and Th1/Th2 balance, improve cellular and humoral immune functions, inhibit oxidative stress, and reduce recurrences in anal sinusitis patients [29]. b) anti-inflammatory effect: some herbs in LDXGD have anti-inflammatory effects, saikosaponin a, a main bioactive component of Chaihu, Sung found that saikosaponin a modulates the expression of pro-inflammatory and inflammation-related genes in 3T3-L1 hypertrophic adipocytes and is a potent repressor of NF-κB activation. it was inhibition of ERK pathways that prevents the induction of inflammation in hypertrophic adipocytes [30]. In addition, Huangqin can block the arachidonic acid pathway from different links [31, 32], inhibit the secretion of cytokines, so as to achieve an anti-inflammatory effect[33].c) antibacterial and anti-viral: LDXGD can inhibit mycoplasma, and fungal and bacterial infections [34-36]. Li’s experimental results show that LDXGD treating on cervicitis patients with human papillomavirus infection, and the total effective rate was 93.18% [37], which demonstrated an inhibitory effect on human papillomavirus. d) analgesic effect: LDXGD and its herbal components such as Chai Hu, Longdancao, Zhizi and Huangqin have better analgesic effects [38]. Xu indicated that LDXGD is more effective than pregabalin in the treatment of postherpetic neuralgia of the head and face [39]. Zhang et al. found that 8-O-acetyl-safalinoside can effectively alleviate chronic inflammatory pain in rats, and the mechanism may be related to the inhibition of p38 MAPK phosphorylation and the expression of IL-6, IL-1β, and TNF-α [40].
Limitations for the Review
In this meta-analysis of chronic prostatitis, LDXGD was shown to have beneficial effects. However, there were some limitations. First, although all included studies reported randomization, only 4 studies used the random number table. 4 of the 12 studies used treatment method grouping or date of visit. Furthermore, all trials had some defects, such as not disclosing details in random allocation, outcome assessors, blinding participants, and personnel, and reporting selective outcomes. Secondly, six studies used modified LDXGD that was not exactly representative of LDXGD's effect. Thirdly, the adverse reactions of LDXGD on chronic prostatitis are unknown because only one study described the adverse events.
In summary, this meta-analysis identified that LDXGD can improve the clinical cure rate and the total effective rate of chronic prostatitis patients and reduce the NIH-CPSI score and EPS-WBC count. At the same time, LDXGD can improve the quality of life of patients. To provide stronger evidence for the treatment of chronic prostatitis with LDXGD, more rigorous designs of standardized research are needed.
Chronic prostatitis
lower urinary tract symptoms
National Institutes of Health
NIH-Chronic Prostatitis Symptom Index
Longdanxiegan decoction
LDXGD plus antibiotics
China Biology Medicine disc
China national knowledge infrastructure
relative risk
confidence interval
mean difference
expressed as prostatic secretion-white blood cell.
Acknowledgements
Not applicable.
Funding
This work was supported by renal protection based TCM protocol for allergic purpura (Ref 2021YJ0153). Funding is provided by Sichuan Province Science and Technology Support Program.
Availability of data and materials
Not applicable.
Authors’ contributions
HC, XS, FZ, and YW provided the study concept and design. HC, XS, and YW searched databases, screened these articles, and extracted the data. HC, XS, and YW were involved in data analysis, interpretation, and disagreement resolution. HC and XS drafted the paper. XS and FZ supervised the study. The final manuscript was approved by all authors. HC and XS contributed equally to this work.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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Tables 1 and 2 are available in the Supplementary Files section