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Clinical Review |

Management of Chronic Prostatitis/ Chronic Pelvic Pain Syndrome:  A Systematic Review and Network Meta-analysis FREE

Thunyarat Anothaisintawee, MD; John Attia, MD, PhD, FRCPC; J. Curtis Nickel, MD, FRCSC; Sangsuree Thammakraisorn, MD; Pawin Numthavaj, MD; Mark McEvoy, MSc; Ammarin Thakkinstian, PhD
[+] Author Affiliations

Author Affiliations: Section for Clinical Epidemiology and Biostatistics (Drs Anothaisintawee, Numthavaj, and Thakkinstian) and Department of Family Medicine (Drs Anothaisintawee and Thammakraisorn), Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle (Dr Attia and Mr McEvoy), and Hunter Medical Research Institute (Dr Attia), Newcastle, New South Wales, Australia; and Department of Urology, Queens University, Kingston, Ontario, Canada (Dr Nickel).


JAMA. 2011;305(1):78-86. doi:10.1001/jama.2010.1913.
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Published online

Context Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is common, but trial evidence is conflicting and therapeutic options are controversial.

Objective To conduct a systematic review and network meta-analysis comparing mean symptom scores and treatment response among α-blockers, antibiotics, anti-inflammatory drugs, other active drugs (phytotherapy, glycosaminoglycans, finasteride, and neuromodulators), and placebo.

Data Sources We searched MEDLINE from 1949 and EMBASE from 1974 to November 16, 2010, using the PubMed and Ovid search engines.

Study Selection Randomized controlled trials comparing drug treatments in CP/CPPS patients.

Data Extraction Two reviewers independently extracted mean symptom scores, quality-of-life measures, and response to treatment between treatment groups. Standardized mean difference and random-effects methods were applied for pooling continuous and dichotomous outcomes, respectively. A longitudinal mixed regression model was used for network meta-analysis to indirectly compare treatment effects.

Data Synthesis Twenty-three of 262 studies identified were eligible. Compared with placebo, α-blockers were associated with significant improvement in symptoms with standardized mean differences in total symptom, pain, voiding, and quality-of-life scores of −1.7 (95% confidence interval [CI], −2.8 to −0.6), −1.1 (95% CI, −1.8 to −0.3), −1.4 (95% CI, −2.3 to −0.5), and −1.0 (95% CI, −1.8 to −0.2), respectively. Patients receiving α-blockers or anti-inflammatory medications had a higher chance of favorable response compared with placebo, with pooled RRs of 1.6 (95% CI, 1.1-2.3) and 1.8 (95% CI, 1.2-2.6), respectively. Contour-enhanced funnel plots suggested the presence of publication bias for smaller studies of α-blocker therapies. The network meta-analysis suggested benefits of antibiotics in decreasing total symptom scores (−9.8; 95% CI, −15.1 to −4.6), pain scores (−4.4; 95% CI, −7.0 to −1.9), voiding scores (−2.8; 95% CI, −4.1 to −1.6), and quality-of-life scores (−1.9; 95% CI, −3.6 to −0.2) compared with placebo. Combining α-blockers and antibiotics yielded the greatest benefits compared with placebo, with corresponding decreases of −13.8 (95% CI, −17.5 to −10.2) for total symptom scores, −5.7 (95% CI, −7.8 to −3.6) for pain scores, −3.7 (95% CI, −5.2 to −2.1) for voiding, and −2.8 (95% CI, −4.7 to −0.9) for quality-of-life scores.

Conclusions α-Blockers, antibiotics, and combinations of these therapies appear to achieve the greatest improvement in clinical symptom scores compared with placebo. Anti-inflammatory therapies have a lesser but measurable benefit on selected outcomes. However, beneficial effects of α-blockers may be overestimated because of publication bias.

Figures in this Article

Prostatitis is a common condition, with an estimated prevalence in the community of about 9%,1 and accounts for nearly 2 million ambulatory care encounters annually in the United States.2 However, prostatitis represents a heterogeneous mix of conditions, including acute prostatitis, chronic bacterial prostatitis, and asymptomatic inflammatory prostatitis. Quiz Ref IDChronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), which accounts for 90% to 95% of cases,3,4 is a clinical entity defined as urologic pain or discomfort in the pelvic region, associated with urinary symptoms and/or sexual dysfunction, lasting for at least 3 of the previous 6 months. Chronic prostatitis/chronic pelvic pain syndrome is a diagnosis of exclusion that can be made after ruling out active urethritis, urogenital cancer, urinary tract disease, urethral stricture, or neurological disease affecting the bladder. Symptoms of CP/CPPS can diminish quality of life and impair physical and psychological function.5

Quiz Ref IDThe etiology of CP/CPPS is uncertain but may include inflammatory or noninflammatory etiologies.68 An inciting agent may cause inflammation or neurological damage in or around the prostate and lead to pelvic floor neuromuscular and/or neuropathic pain. Predisposing factors for CP/CPPS may include heredity, infection, voiding abnormalities, hormone imbalance, intraprostatic reflux, immunological or allergic triggers, or psychological traits. A wide variety of therapies including α-blockers, antibiotics, anti-inflammatory medications, and other agents (eg, finasteride, phytotherapy, and gabapentinoids) are routinely used. However, the efficacy of these treatments is controversial,915 partly because many clinical trials testing these therapies have been small, with little statistical power to detect treatment effects.

To date, only 1 systematic review6 and 1 meta-analysis16 of α-blockers vs placebo of which we are aware have been performed for treatment of CP/CPPS. We therefore performed a systematic review and network meta-analysis mapping all treatment regimens, with 2 aims. First, we compared total symptom, pain, voiding, and quality-of-life scores at the end of therapy with α-blockers (the most commonly evaluated therapy for CP/CPPS), other active drugs, or placebo. Second, we compared rates of responses to therapies available for treating CP/CPPS.

Search Strategy

We searched the MEDLINE and EMBASE databases for relevant studies published in English from 1949 (for MEDLINE) or 1974 (for EMBASE) through November 16, 2010. Search terms and strategies for each database are described in the eAppendix. Reference lists of included trials and the previous systematic reviews6,16 were explored.

Selection of Studies

Identified studies were selected based on title and abstract by 2 independent authors (T.A. and S.T.). Full articles were retrieved if a decision could not be made based on the abstracts. Agreement between the 2 reviewers was measured using the κ statistic. Disagreement was resolved by consensus and by discussion with a third party (J.C.N. or A.T.).

Inclusion Criteria

Randomized controlled trials that were published in English were selected if they met the following criteria: (1) Participants met criteria for CP/CPPS categories IIIA or IIIB according to the National Institutes of Health classification.4 (2) The study compared any pair of the following interventions: α-blockers, antibiotics, steroidal and nonsteroidal anti-inflammatory drugs, finasteride, glycosminoglycans, phytotherapy, gabapentinoids, and placebo. (3) The study measured any of the following outcomes: pain scores, voiding scores, quality-of-life scores, and total symptom scores. The total symptom score is a summation of pain, voiding, and quality-of-life scores. (4) The full article could be retrieved and had sufficient data for extraction, including number of patients, means and standard deviations of continuous outcomes in each group, and/or numbers of patients per group for dichotomous outcomes.

Data Extraction

Two authors (T.A. and S.T.) independently extracted data using a standardized extraction form. Disagreement was resolved by discussion or consensus with a third party (A.T.). Missing information was sought by contacting the corresponding authors of the studies.

Risk of Bias Assessment

Two authors (T.A and P.N.) independently assessed risk of bias of each study using an established tool.17 Six domains were assessed: sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias. Disagreement between 2 authors was resolved by consensus and discussion. Levels of agreement for each domain and the overall domains were assessed using the κ statistic.

Outcomes

The outcomes of interests were total symptom, pain, voiding, and quality-of-life scores and response rates as defined in the original articles. The following tools were used in these assessments: (1) The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) consists of 3 domains (ie, pain, voiding, and quality of life). The total scores range from 0 to 43.18 (2) The International Prostate Symptom Score (IPSS) questionnaire19 consists of 3 domains (ie, pain, voiding, and quality of life), with combined scores ranging from 0 to 51. (3) The Prostatitis Symptom Score Index (PSSI) measures only pain scores, with a total score of 0 to 12. (4) Other pain and voiding questionnaires20 consist of 7 and 5 items, respectively, with each item graded as 0 to 3.

For each measurement, scores closer to 0 reflect more favorable status. The minimal clinical significant difference for all these scales is 3 to 6 points.2124 For response to treatment, various definitions were used in the original studies; eg, 25%, 33%, or 50% decreases in the NIH-CPSI or 4 (clinically perceptible improvement) to 6 (clinically significant improvement) unit score decreases in the NIH-CPSI from baseline.

Statistical Analysis

For the direct meta-analysis, mean differences of continuous outcomes (ie, total symptom, pain, voiding, and quality-of-life scores) between treatment groups were estimated for each study and were pooled using a standardized mean difference (SMD) if the scales used for outcome measures differed. Otherwise, an unstandardized mean difference (USMD) was applied. Heterogeneity of the mean difference was assessed using Q and I2 statistics. If heterogeneity was present or the degree of heterogeneity (I2) was greater than 25%, the SMD was estimated using a random-effects model. Otherwise, a fixed-effects model was applied.

Relative risks (RRs) of response to treatment were estimated for each study. If there was evidence of heterogeneity, a random-effects model was used for pooling. Otherwise, the inverse-variance method was used. The source of heterogeneity was explored by fitting covariables (ie, mean age, duration of treatment, and baseline total symptom scores) one by one in the meta-regression. Publication bias was assessed using contour-enhanced funnel plots and the Egger test.25,26

For indirect comparisons, network meta-analyses were applied to assess treatment effects for all possible treatment groups if summary data were available.2729 Linear regression models weighted by inverse variance were applied to assess treatment effects for continuous outcomes. Effects of study were included as covariates in the model. For response to treatment, summary data were expanded to individual patient-level data using the “expand” command in Stata. Treatment groups were considered in a mixed-effect hierarchical model with a log-link function using the “xtpoisson” command.27 Pooled RRs and 95% confidence intervals (CIs) were estimated by exponential coefficients of treatments. All analyses were performed using Stata software, version 11.0.30 Two-sided P <.05 was considered statistically significant except for the heterogeneity test, in which a 1-sided P < .10 was used.

Among 262 identified studies, 25 studies were eligible for inclusion (Figure). Two studies31,32 had insufficient data (ie, did not report means and standard deviations). For these studies, one corresponding author31 was contacted for additional information but did not respond, while the author of the other study32 could not be contacted. This left 23 studies915,21,22,24,3345 with sufficient data for extraction. Agreement on study selection between the 2 reviewers was high at 98% (κ = 0.91; P < .001). Disagreements were present for 5 studies (selected by one reviewer but not the other) and included 2 duplicate reports, 1 non–randomized controlled trial, 1 protocol report, and 1 study with mixed CP/CPPS and bacterial prostatitis patients.

Place holder to copy figure label and caption
Figure. Study Selection
Graphic Jump Location

CP/CPPS indicates chronic prostatitis/chronic pelvic pain syndrome.

Twenty studies915,22,24,3335,3741,4345 compared outcomes between 1 active treatment and placebo (Table 1). These treatments were α-blockers in 7 studies,9,10,24,3335,38 antibiotics in 2 studies,39,44 finasteride in 2 studies,37,40 anti-inflammatory drugs in 4 studies,11,12,22,43 phytotherapy in 3 studies,1315 glycosaminoglycan in 1 study,41 and pregabalin in 1 study.45 Three studies21,36,42 had more than 2 treatment groups as follows: α-blockers plus antibiotics, α-blockers alone, and antibiotics alone in 2 studies36,42; and α-blockers plus antibiotics, α-blockers alone, antibiotics alone, and placebo in 1 study.21 Treatment duration ranged from 4 to 52 weeks. Most studies used NIH-CPSI scores for measurement of outcomes. Mean age of participants ranged from 29.1 to 56.1 years.

Table Graphic Jump LocationTable 1. Characteristics of Included Studies

eTable 1 reports the quality assessments of included studies. The agreement between 2 reviewers for each bias assessment domain ranged from 56% to 100% and the overall agreement was 91%. The highest quality was in the domain of selective outcome reports (95.7% low-risk) followed by blinding (87.4%). The lowest quality was in allocation concealment (adequate in 21.7%).

Direct Meta-analysis

Pooled Mean Scores. Eight studies compared mean scores between α-blockers and placebo. Among them, 4 studies10,3335 reported mean scores at follow-up, while the remainder9,21,24,38 reported change in mean score. Among the latter, 2 studies9,21 reported information that allowed data simulation and pooling.9,10,21,33,34

Three studies21,39,44 compared antibiotics with placebo and 3 studies1315 compared phytotherapy with placebo.

Total Symptom Scores. Five studies9,10,21,33,34 (n = 568) comparing α-blockers and placebo were pooled (Table 2). Total symptom scores were assessed at the end of treatment, which ranged from 6 to 24 weeks. Mean differences and 95% CIs are shown in eFigure 1A. The total symptom score SMD in the α-blocker group vs the placebo group was −1.7 (95% CIs, −2.8 to −0.6), with high heterogeneity (I2 = 96.4%). This is equivalent to −5.5 (95% CI, −10.0 to −0.9) units on the NIH-CPSI or IPSS scales. Meta-regression did not identify the source of heterogeneity. Sensitivity analysis was performed by pooling the 4 studies9,21,33,34 with adequate sequence generation of randomization. In this analysis, the treatment effect was still significant, with a USMD of −4.0 (95% CI, −6.4 to −1.6). The Egger test indicated the presence of publication bias (coefficient = −9.3; SE, 2.5; P = .03) (eFigure 2A). Adjusting for publication bias using regression-based analysis resulted in no evidence of treatment benefit (coefficient = 0.47; P = .39).

Table Graphic Jump LocationTable 2. Mean Symptom Scores at the End of Therapy According to Treatment

Three studies21,39,44 (n = 215) were pooled to compare antibiotics with placebo (Table 2). The USMD was −5.8 (95% CI, −15.9 to 4.4). That is, the mean total symptom score in the antibiotic group was 5.8 units lower on the NIH-CPSI scale than in the placebo group, but this did not reach statistical significance (P = .26).

Pain Scores. Six studies9,10,21,3335 (n = 637) compared mean pain scores between α-blockers and placebo (Table 2 and eFigure 1B). The SMD in the random-effects model was −1.1 (95% CI, −1.8 to −0.3). Patients receiving α-blockers had a 1.1-unit (equivalent to 2.2 points for the NIH-CPSI or 1.9 points for the PSSI/pain questionnaire) significantly lower pain score than patients who received placebo, but this was highly heterogeneous across studies (I2 = 94%). The source of this heterogeneity was not apparent. A sensitivity analysis limited to the 4 studies9,21,33,34 with adequate sequence generation yielded an SMD of −0.3 (95% CI, −0.5 to −0.1). The Egger test suggested publication bias due to small-study effect (coefficient = −8.9; P = .02) (eFigure 2B). Adjusting for this bias removed the beneficial effect of α-blockers (coefficient = 1.2; 95% CI, −0.1 to 2.4; P = .06).

Three studies21,39,44 with a total of 215 patients compared mean pain scores between antibiotics and placebo. The USMD was −2.7 (95% CI, −8.7 to 3.2); ie, the mean pain score in the antibiotic group was 2.7 NIH-CPSI units lower than in the placebo group, a difference that was not statistically significant (Table 2). There was no evidence of publication bias (coefficient = −9.3; SE, 4.2; P = .27).

Three studies1315 comparing phytotherapy and placebo were pooled (n = 222). The SMD was −0.5 (95% CI, −0.7 to −0.2); ie, patients receiving phytotherapy had a 0.5-unit significantly lower pain score than patients receiving placebo (Table 2). There was no evidence of publication bias (coefficient = −2.0; P = .08).

Voiding Scores. Five studies9,10,21,33,34 compared α-blockers and placebo for the outcome of voiding scores (n = 568). In the random-effects model, the SMD was −1.4 (95% CI, −2.3 to −0.5). That is, the mean voiding scores were 1.4 units significantly lower in the α-blocker groups than in the placebo groups (Table 2 and eFigure 1C). This difference translates into 3.1 units on the NIH-CPSI and IPSS scales. In sensitivity analyses limited to the 4 studies9,21,33,34 with adequate randomization, the SMD was −0.7 (95% CI, −1.2 to −0.2). The Egger test suggested publication bias due to small-study effects (coefficient = −9.5; P = .02). The contour-enhanced funnel plot indicated asymmetry (eFigure 2C), and adjusting for this bias removed any favorable treatment effect (coefficient = 1.1; 95% CI, −0.4 to 2.6; P = .10).

Three studies21,39,44 comparing antibiotics and placebo (n = 215) had a pooled SMD of −3.2 (95% CI, −6.1 to −0.3) (Table 2). Three studies comparing phytotherapy with placebo (n = 223)1315 had an SMD of −0.4 (95% CI, −0.7 to −0.1) (Table 2).

Quality-of-Life Scores. Five studies compared quality-of-life scores between α-blocker and placebo groups (n = 568).9,10,21,33,34 The SMD was −1.0 (95% CI, −1.8 to −0.2) (or approximately 1.4 units on the NIH-CPSI and IPSS scales) lower in the α-blocker group than in the placebo group. However, results were heterogeneous (eFigure 1D). The contour-enhanced funnel plot suggested publication bias from 2 small studies10,34 that had strong treatment effects (eFigure 2D); adjusting for this bias removed the significant benefit of α-blockers (coefficient = 1.2; 95% CI, −0.6 to 2.9; P = .13).

Three studies21,39,44 (n = 215) compared quality of life between antibiotics and placebo. The estimated USMD was −1.5 (95% CI, −3.6 to 0.6) NIH-CPSI units lower in antibiotics groups than placebo groups, but this difference was not statistically significant (Table 2). The Egger test did not suggest publication bias (coefficient = −13.2; SE, 2.7; P = .13).

Pooled Response Rate. Nine studies9,10,12,21,22,24,33,38,43 included a dichotomized treatment response as the outcome of interest. Of these, 6 studies9,10,21,24,33,38 compared α-blockers with placebo and 3 studies12,22,43 compared anti-inflammatory drugs with placebo. Among 6 studies (n = 602) comparing α-blockers with placebo, various criteria were used for assessing treatment responses (Table 3). The pooled RR was 1.6 (95% CI, 1.1-2.3); ie, patients receiving α-blockers were 60% more likely to have a response than patients receiving placebo (eFigure 3A). However, there was moderately high heterogeneity. Meta-regression evaluating duration of treatment reduced the I2 from 64.2% to 12.8%, indicating that treatment duration may explain the heterogeneity (eFigure 3A). Duration of treatment was 6 to 12 weeks in 3 studies9,21,24 and 14 to 24 weeks in the other 3 studies.10,33,38 Pooled RRs within these subgroups were homogeneous (eFigure 3A) at1.0 (95% CI, 0.8-1.3) for 6 to 12 weeks' duration and 2.0 (95% CI, 1.4-3.0) for 14 to 24 weeks' duration, respectively.

Table Graphic Jump LocationTable 3. Treatment Response Rates for α-Blockers and Anti-inflammatory Drugs

The contour-enhanced funnel plot suggested asymmetry, especially within the 3 studies in which treatment duration ranged from 14 to 24 weeks (eFigure 3B). Metatrim indicated that 3 studies with negative effects of α-blockers were missing. Adding these studies into pooling yielded no benefit from α-blockers, with a pooled RR of 1.1 (95% CI, 0.8-1.7).

Three studies12,22,43 were pooled to compare anti-inflammatory therapies with placebo (n = 190). The types of anti-inflammatory drugs were cyclooxygenase 2 inhibitors in 2 studies12,43 and a corticosteroid in 1 study.22 The pooled RR was 1.8 (95% CI, 1.2-2.6), with mild heterogeneity (I2 = 24.4%). These results indicate that patients receiving anti-inflammatory drugs were 80% more likely to have a favorable response than patients receiving placebo (Table 3). The Egger test did not suggest publication bias (coefficient = −0.36; P = .90).

Network Meta-analysis

Total Symptom Scores. Data from 13 studies (n = 1541)9,10,14,15,21,33,3945 using the NIH-CPSI were included in network meta-analyses for the outcome of total symptom score (eTable 2). Treatment comparisons are described in eTable 3 and eFigure 4. Mean total scores at follow-up were, for α-blockers, −11.0 (95% CI, −13.9 to −8.1), for antibiotics, −9.8 (95% CI, −15.1 to −4.6), for α-blockers plus antibiotics, −13.8 (95% CI, −17.5 to −10.2), and for finasteride, −4.6 (95% CI, −8.7 to −0.5) units significantly lower than placebo groups. In this instance, α-blockers plus antibiotics were better than any other therapy and were significantly better than α-blockers alone (−2.9; 95% CI, −5.2 to −0.5).

Pain Scores. The network meta-analysis was performed with 14 studies911,1315,21,33,39,4145 that used similar NIH-CPSI scores (eTable 2). α-Blockers, antibiotics, α-blockers plus antibiotics, and anti-inflammatory drugs were associated with significantly better pain scores at follow-up than placebo, with pain scores of −4.1 (95% CI, −5.9 to −2.3), −4.4 (95% CI, −7.0 to −1.9), −5.7 (95% CI, −7.8 to −3.6), and −3.0 (95% CI, −5.7 to −0.4), respectively (eTable 3 and eFigure 5). Again, the most favorable therapy was α-blockers plus antibiotics (eFigure 5).

Voiding Scores. Thirteen studies9,10,1315,21,33,39,4145 (n = 631) were included in the voiding analysis (eTable 2 and eFigure 6). Mean voiding scores at follow-up for α-blockers, antibiotics, and α-blockers plus antibiotics were −3.4 (95% CI, −4.8 to −2.1), −2.8 (95% CI, −4.1 to −1.6), and −3.7 (95% CI, −5.2 to −2.1) units significantly lower than for placebo (eTable 3). Again, the best treatment in the network comparisons was α-blockers plus antibiotics.

Quality-of-Life Scores. Twelve studies (n = 1477)9,10,14,15,21,33,39,4145 were included in the quality-of-life analysis (eTable 2). Associations of α-blockers, antibiotics, and α-blockers plus antibiotics (−1.9; 95% CI, −3.6 to −0.2) were significantly better than placebo (eTable 3 and eFigure 7). α-Blockers plus antibiotics was the best treatment in the network comparisons, with a decrease of −2.8 (95% CI, −4.7 to −0.9) units in the quality-of-life score.

Response Rate. Fourteen studies9,10,12,15,21,22,24,33,36,3840,43,45 (n = 1561) reported favorable response to treatment (eFigure 8 and eTable 4). The RR of treatment response was highest with anti-inflammatory drugs (RR, 1.8; 95% CI, 1.3-2.6), followed by phytotherapy (RR, 1.6; 95% CI, 1.1-2.4) and α-blockers (RR, 1.3; 95% CI, 1.0-1.6) compared with placebo (eTable 5). Anti-inflammatory therapies were the best treatment in the network comparisons.

We performed a systematic review and meta-analysis of outpatient treatments for CP/CPPS. We studied relevant clinical outcomes, including total clinical symptom, voiding, pain, and quality-of-life scores, as well as treatment response rates. Quiz Ref IDα-Blockers, antibiotics, and a combination of the 2 appear to improve all clinical symptom scores compared with placebo, while anti-inflammatory drugs, finasteride, and phytotherapies have a lesser but measureable effect on select variables (ie, pain, voiding symptoms, and treatment response rate, respectively). However, the treatment effects of α-blockers are distorted by publication bias/small-study effects, and adjusting for this removes any treatment benefit.

Given the large number of treatment options, meta-analyses of direct comparisons are limited by the small number of studies that evaluated a particular pair of treatments. Network meta-analysis circumvents this problem by creating indirect comparisons and allowing data synthesis that can help identify the most effective therapy. In this case, α-blockers plus antibiotics was consistently the best therapy when the outcome was symptom scores. Anti-inflammatory drugs were the best therapy when treatment response was the outcome; although steroids and nonsteroidal anti-inflammatory drugs were pooled together because of the small number of studies, the heterogeneity was low, indicating that their effects may be similar.

Quiz Ref IDTreatment benefits (whether we measured effect on symptom scores or responder rates) were modest for some therapies and nonexistent for others. This probably reflects the heterogeneous nature of patients presenting with CP/CPPS. Patients with CP/CPPS represent a group of divergent clinical phenotypes based on the various etiologies and pathogenic pathways that underlie this enigmatic condition.46 As a result of difficulties in diagnoses, some patients (in clinical trials and practice) likely receive inappropriate therapies. It makes clinical sense that patients with predominant voiding dysfunction may respond best to α-blockers, those with a history of urinary tract infection may respond best to antibiotics, and those with pain/inflammation may respond best to anti-inflammatory drugs and/or gabapentinoids. However, further study is needed to determine whether patient characteristics determine the most effective therapy for CP/CPPS.

Because the diagnosis of CP/CPPS requires exclusion of infection, the reason for the benefit associated with antibiotics is not immediately clear. This observed effect may be due to the eradication or suppression of uncultured or unrecognized uropathogens that may be measurable with polymerase chain reaction.4749 In addition, it is important to point out that quinolones have anti-inflammatory50,51 and analgesic properties.52

While the results of our analyses demonstrate that α-blockers, antibiotics, and anti-inflammatory medications are beneficial for CP/CPPS, we recognize that the total sample sizes are relatively small and that the effect sizes are modest and often below the minimal clinically significant difference. Furthermore, even these estimates may be overinflated given the evidence for publication bias. Our results suggest that future research should focus on using these treatments rationally, perhaps using individualized patient therapy or multiple therapies directed toward the specific clinical phenotype of each unique patient.53 This concept is presently being evaluated.49Quiz Ref IDThe decision to use these therapies also needs to take account of the adverse event profile: α-blockers can cause postural hypotension, edema, and drowsiness; quinolones can cause dizziness, headaches, and gastrointestinal upset; and nonsteroidal anti-inflammatory drugs can cause gastritis, renal impairment, and edema. The risk-benefit ratio remains to be determined.

Our study has several strengths. The review methods were systematic and exhaustive. Contour-enhanced funnel plots helped to identify possible publication bias due to small-study effects, which tend to lead to higher treatment effects than large studies.25,26 We mapped all possible treatment comparisons (9 treatments with 36 possible pairwise comparisons) using a network meta-analysis.2729 An advantage of network meta-analysis is the ability to “borrow” information on the treatment groups from other studies, thereby increasing the total sample sizes. For example, direct comparisons in a previous meta-analysis16 included 466, 236, and 123 patients in pooling for total symptom, pain, and voiding scores, respectively, comparing α-blockers vs placebo. In the current analysis, the corresponding numbers of patients were 1549, 1556, and 1546. We applied a mixed model, which is thought to be the most appropriate method for network meta-analysis.27,54 Although our pooled estimates were quite heterogeneous, the mixed model with random intercept takes into account variations at the study level.

These methods have limitations, however. Although all studies were randomized controlled trials, most studies were unclear in randomization sequence generations and, hence, selection bias or confounding might be present. Pooled results were often heterogeneous and the source of this difference was not apparent.

Our review suggests that α-blockers, antibiotics, or combinations of both are most appropriate for therapy of CP/CPPS, particularly for patients with voiding symptoms. However, the magnitude of apparent benefit with α-blockers may be distorted by publication bias. Anti-inflammatory medications remain an option for patients presenting with pain. While finasteride and phytotherapy may provide benefit to some patients, these therapies require more evaluation, perhaps in selected subgroups of CP/CPPS patients.

Corresponding Author: Ammarin Thakkinstian, PhD, Section for Clinical Epidemiology and Biostatistics, Ramathibodi Hospital, Rama VI Rd, Rachatevi, Bangkok, Thailand 10400 (raatk@mahidol.ac.th).

Author Contributions: Dr Thakkinstian had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Thakkinstian.

Acquisition of data: Anothaisintawee, Thammakraisorn, Numthavaj, Thakkinstian.

Analysis and interpretation of data: Anothaisintawee, Attia, Nickel, McEvoy, Thakkinstian.

Drafting of the manuscript: Anothaisintawee, Thakkinstian.

Critical revision of the manuscript for important intellectual content: Attia, Nickel, Thammakraisorn, Numthavaj, McEvoy, Thakkinstian.

Statistical analysis: Anothaisintawee, Thakkinstian.

Administrative, technical, or material support: Thammakraisorn, Numthavaj, Thakkinstian.

Study supervision: Attia, Nickel, Thakkinstian.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Nickel reported serving as a consultant for GlaxoSmithKline, Pfizer, Watson, Farr Labs, Astellas, and Triton and as an investigator for GlaxoSmithKline, Pfizer, and Watson. No other authors reported disclosures.

Funding/Support: Dr Nickel's research in CP/CPPS is funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, the Canada Institute for Health Research, and the Canada Research Chair Program.

Role of the Sponsor: None of the funding organizations or sponsors had any role in the design and conduct of the study; the extraction, management, analysis, or interpretation of the data; or the preparation, review, or approval of the manuscript.

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PubMed   |  Link to Article
Collins MM, Stafford RS, O’Leary MP, Barry MJ. How common is prostatitis?  J Urol. 1998;159(4):1224-1228
PubMed   |  Link to Article
de la Rosette JJ, Hubregtse MR, Meuleman EJ,  et al.  Diagnosis and treatment of 409 patients with prostatitis syndromes.  Urology. 1993;41(4):301-307
PubMed   |  Link to Article
Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis.  JAMA. 1999;282(3):236-237
PubMed   |  Link to Article
McNaughton Collins M, Pontari MA, O’Leary MP,  et al; Chronic Prostatitis Collaborative Research Network.  Quality of life is impaired in men with chronic prostatitis.  J Gen Intern Med. 2001;16(10):656-662
PubMed   |  Link to Article
McNaughton Collins M, MacDonald R, Wilt TJ. Diagnosis and treatment of chronic abacterial prostatitis.  Ann Intern Med. 2000;133(5):367-381
PubMed   |  Link to Article
Hetrick DC, Ciol MA, Rothman I,  et al.  Musculoskeletal dysfunction in men with chronic pelvic pain syndrome type III.  J Urol. 2003;170(3):828-831
PubMed   |  Link to Article
Hochreiter WW, Nadler RB, Koch AE,  et al.  Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions.  Urology. 2000;56(6):1025-1029
PubMed   |  Link to Article
Nickel JC, Krieger JN, McNaughton-Collins M,  et al; Chronic Prostatitis Collaborative Research Network.  Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome.  N Engl J Med. 2008;359(25):2663-2673
PubMed   |  Link to Article
Tuğcu V, Taşçi AI, Fazlioğlu A,  et al.  A placebo-controlled comparison of the efficiency of triple- and monotherapy in category III B chronic pelvic pain syndrome (CPPS).  Eur Urol. 2007;51(4):1113-1117
PubMed   |  Link to Article
Goldmeier D, Madden P, McKenna M, Tamm N. Treatment of category III A prostatitis with zafirlukast: a randomized controlled feasibility study.  Int J STD AIDS. 2005;16(3):196-200
PubMed   |  Link to Article
Nickel JC, Pontari M, Moon T,  et al; Rofecoxib Prostatitis Investigator Team.  A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis.  J Urol. 2003;169(4):1401-1405
PubMed   |  Link to Article
Elist J. Effects of pollen extract preparation Prostat/Poltit on lower urinary tract symptoms in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized, double-blind, placebo-controlled study.  Urology. 2006;67(1):60-63
PubMed   |  Link to Article
Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis.  Urology. 1999;54(6):960-963
PubMed   |  Link to Article
Wagenlehner FM, Schneider H, Ludwig M,  et al.  A pollen extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome.  Eur Urol. 2009;56(3):544-551
PubMed   |  Link to Article
Yang G, Wei Q, Li H,  et al.  The effect of α-adrenergic antagonists in chronic prostatitis/chronic pelvic pain syndrome.  J Androl. 2006;27(6):847-852
PubMed   |  Link to Article
Higgins JPT, Altman DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons; 2008
Litwin MS, McNaughton-Collins M, Fowler FJ Jr,  et al; Chronic Prostatitis Collaborative Research Network.  The National Institutes of Health Chronic Prostatitis Symptom Index.  J Urol. 1999;162(2):369-375
PubMed   |  Link to Article
Cockett ATK, Khoury S, Aso Y,  et al.  Second International Consultation on Benign Prostatic Hyperplasia. Hong Kong: Scientific Communications International; 1994:624-635
Krieger JN, Egan KJ, Ross SO,  et al.  Chronic pelvic pains represent the most prominent urogenital symptoms of “chronic prostatitis.”  Urology. 1996;48(5):715-721
PubMed   |  Link to Article
Alexander RB, Propert KJ, Schaeffer AJ,  et al; Chronic Prostatitis Collaborative Research Network.  Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome.  Ann Intern Med. 2004;141(8):581-589
PubMed   |  Link to Article
Bates SM, Hill VA, Anderson JB,  et al.  A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome.  BJU Int. 2007;99(2):355-359
PubMed   |  Link to Article
Nickel JC. Treatment of chronic prostatitis/chronic pelvic pain syndrome.  Int J Antimicrob Agents. 2008;31:(suppl 1)  S112-S116
PubMed   |  Link to Article
Nickel JC, Narayan P, McKay J, Doyle C. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin.  J Urol. 2004;171(4):1594-1597
PubMed   |  Link to Article
Moreno SG, Sutton AJ, Turner EH,  et al.  Novel methods to deal with publication biases.  BMJ. 2009;339:b2981
PubMed   |  Link to Article
Nüesch E, Trelle S, Reichenbach S,  et al.  Small study effects in meta-analyses of osteoarthritis trials.  BMJ. 2010;341:c3515
PubMed   |  Link to Article
Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons.  Stat Med. 2004;23(20):3105-3124
PubMed   |  Link to Article
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions.  BMJ. 2003;326(7387):472
PubMed   |  Link to Article
Song F, Harvey I, Lilford R. Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions.  J Clin Epidemiol. 2008;61(5):455-463
PubMed   |  Link to Article
 Stata [computer program]. Release 11. College Station, TX: Stata Corp; 2009
Kaplan SA, Volpe MA, Te AE. A prospective, 1-year trial using saw palmetto vs finasteride in the treatment of category III prostatitis/chronic pelvic pain syndrome.  J Urol. 2004;171(1):284-288
PubMed   |  Link to Article
Kulovac B, Aganović D, Prcić A, Hadziosmanović O. Management of chronic nonbacterial prostatitis/chronic pelvic pain syndrome.  Bosn J Basic Med Sci. 2007;7(3):245-249
PubMed
Cheah PY, Liong ML, Yuen KH,  et al.  Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome.  J Urol. 2003;169(2):592-596
PubMed   |  Link to Article
Evliyaoğlu Y, Burgut R. Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with α-blocking agent doxazosin; vs placebo.  Int Urol Nephrol. 2002;34(3):351-356
PubMed   |  Link to Article
Gül O, Eroğlu M, Ozok U. Use of terazosine in patients with chronic pelvic pain syndrome and evaluation by Prostatitis Symptom Score Index.  Int Urol Nephrol. 2001;32(3):433-436
PubMed   |  Link to Article
Jeong CW, Lim DJ, Son H,  et al.  Treatment for chronic prostatitis/chronic pelvic pain syndrome: levofloxacin, doxazosin and their combination.  Urol Int. 2008;80(2):157-161
PubMed   |  Link to Article
Leskinen M, Lukkarinen O, Marttila T. Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome.  Urology. 1999;53(3):502-505
PubMed   |  Link to Article
Mehik A, Alas P, Nickel JC,  et al.  Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome.  Urology. 2003;62(3):425-429
PubMed   |  Link to Article
Nickel JC, Downey J, Clark J,  et al.  Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men.  Urology. 2003;62(4):614-617
PubMed   |  Link to Article
Nickel JC, Downey J, Pontari MA,  et al.  A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis).  BJU Int. 2004;93(7):991-995
PubMed   |  Link to Article
Nickel JC, Forrest JB, Tomera K,  et al.  Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome.  J Urol. 2005;173(4):1252-1255
PubMed   |  Link to Article
Ye ZQ, Lan RZ, Yang WM,  et al.  Tamsulosin treatment of chronic non-bacterial prostatitis.  J Int Med Res. 2008;36(2):244-252
PubMed   |  Link to Article
Zhao WP, Zhang ZG, Li XD,  et al.  Celecoxib reduces symptoms in men with difficult chronic pelvic pain syndrome (category IIIA).  Braz J Med Biol Res. 2009;42(10):963-967
PubMed   |  Link to Article
Zhou Z, Hong L, Shen X,  et al.  Detection of nanobacteria infection in type III prostatitis.  Urology. 2008;71(6):1091-1095
PubMed   |  Link to Article
Pontari MA, Krieger JN, Litwin MS,  et al; Chronic Prostatitis Collaborative Research Network-2.  Pregabalin for the treatment of men with chronic prostatitis/chronic pelvic pain syndrome.  Arch Intern Med. 2010;170(17):1586-1593
PubMed   |  Link to Article
Shoskes DA, Nickel JC, Dolinga R, Prots D. Clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity.  Urology. 2009;73(3):538-542
PubMed   |  Link to Article
Nickel JC, Moon T. Chronic bacterial prostatitis.  Urology. 2005;66(1):2-8
PubMed   |  Link to Article
Nickel JC, Xiang J. Clinical significance of nontraditional bacterial uropathogens in the management of chronic prostatitis.  J Urol. 2008;179(4):1391-1395
PubMed   |  Link to Article
Shoskes DA, Nickel JC, Kattan MW. Phenotypically directed multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome.  Urology. 2010;75(6):1249-1253
PubMed   |  Link to Article
Galley HF, Nelson SJ, Dubbels AM, Webster NR. Effect of ciprofloxacin on the accumulation of interleukin-6, interleukin-8, and nitrite from a human endothelial cell model of sepsis.  Crit Care Med. 1997;25(8):1392-1395
PubMed   |  Link to Article
Yoshimura T, Kurita C, Usami E,  et al.  Immunomodulatory action of levofloxacin on cytokine production by human peripheral blood mononuclear cells.  Chemotherapy. 1996;42(6):459-464
PubMed   |  Link to Article
Katsuno G, Takahashi HK, Iwagaki H,  et al.  The immunosuppressive effects of ciprofloxacin during human mixed lymphocyte reaction.  Clin Immunol. 2006;119(1):110-119
PubMed   |  Link to Article
Nickel JC, Shoskes DA. Phenotypic approach to the management of the chronic prostatitis/chronic pelvic pain syndrome.  BJU Int. 2010;106(9):1252-1263
PubMed   |  Link to Article
Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments.  BMJ. 2005;331(7521):897-900
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure. Study Selection
Graphic Jump Location

CP/CPPS indicates chronic prostatitis/chronic pelvic pain syndrome.

Tables

Table Graphic Jump LocationTable 1. Characteristics of Included Studies
Table Graphic Jump LocationTable 2. Mean Symptom Scores at the End of Therapy According to Treatment
Table Graphic Jump LocationTable 3. Treatment Response Rates for α-Blockers and Anti-inflammatory Drugs

References

Roberts RO, Lieber MM, Rhodes T,  et al.  Prevalence of a physician-assigned diagnosis of prostatitis.  Urology. 1998;51(4):578-584
PubMed   |  Link to Article
Collins MM, Stafford RS, O’Leary MP, Barry MJ. How common is prostatitis?  J Urol. 1998;159(4):1224-1228
PubMed   |  Link to Article
de la Rosette JJ, Hubregtse MR, Meuleman EJ,  et al.  Diagnosis and treatment of 409 patients with prostatitis syndromes.  Urology. 1993;41(4):301-307
PubMed   |  Link to Article
Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis.  JAMA. 1999;282(3):236-237
PubMed   |  Link to Article
McNaughton Collins M, Pontari MA, O’Leary MP,  et al; Chronic Prostatitis Collaborative Research Network.  Quality of life is impaired in men with chronic prostatitis.  J Gen Intern Med. 2001;16(10):656-662
PubMed   |  Link to Article
McNaughton Collins M, MacDonald R, Wilt TJ. Diagnosis and treatment of chronic abacterial prostatitis.  Ann Intern Med. 2000;133(5):367-381
PubMed   |  Link to Article
Hetrick DC, Ciol MA, Rothman I,  et al.  Musculoskeletal dysfunction in men with chronic pelvic pain syndrome type III.  J Urol. 2003;170(3):828-831
PubMed   |  Link to Article
Hochreiter WW, Nadler RB, Koch AE,  et al.  Evaluation of the cytokines interleukin 8 and epithelial neutrophil activating peptide 78 as indicators of inflammation in prostatic secretions.  Urology. 2000;56(6):1025-1029
PubMed   |  Link to Article
Nickel JC, Krieger JN, McNaughton-Collins M,  et al; Chronic Prostatitis Collaborative Research Network.  Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome.  N Engl J Med. 2008;359(25):2663-2673
PubMed   |  Link to Article
Tuğcu V, Taşçi AI, Fazlioğlu A,  et al.  A placebo-controlled comparison of the efficiency of triple- and monotherapy in category III B chronic pelvic pain syndrome (CPPS).  Eur Urol. 2007;51(4):1113-1117
PubMed   |  Link to Article
Goldmeier D, Madden P, McKenna M, Tamm N. Treatment of category III A prostatitis with zafirlukast: a randomized controlled feasibility study.  Int J STD AIDS. 2005;16(3):196-200
PubMed   |  Link to Article
Nickel JC, Pontari M, Moon T,  et al; Rofecoxib Prostatitis Investigator Team.  A randomized, placebo controlled, multicenter study to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial prostatitis.  J Urol. 2003;169(4):1401-1405
PubMed   |  Link to Article
Elist J. Effects of pollen extract preparation Prostat/Poltit on lower urinary tract symptoms in patients with chronic nonbacterial prostatitis/chronic pelvic pain syndrome: a randomized, double-blind, placebo-controlled study.  Urology. 2006;67(1):60-63
PubMed   |  Link to Article
Shoskes DA, Zeitlin SI, Shahed A, Rajfer J. Quercetin in men with category III chronic prostatitis.  Urology. 1999;54(6):960-963
PubMed   |  Link to Article
Wagenlehner FM, Schneider H, Ludwig M,  et al.  A pollen extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome.  Eur Urol. 2009;56(3):544-551
PubMed   |  Link to Article
Yang G, Wei Q, Li H,  et al.  The effect of α-adrenergic antagonists in chronic prostatitis/chronic pelvic pain syndrome.  J Androl. 2006;27(6):847-852
PubMed   |  Link to Article
Higgins JPT, Altman DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Chichester, England: John Wiley & Sons; 2008
Litwin MS, McNaughton-Collins M, Fowler FJ Jr,  et al; Chronic Prostatitis Collaborative Research Network.  The National Institutes of Health Chronic Prostatitis Symptom Index.  J Urol. 1999;162(2):369-375
PubMed   |  Link to Article
Cockett ATK, Khoury S, Aso Y,  et al.  Second International Consultation on Benign Prostatic Hyperplasia. Hong Kong: Scientific Communications International; 1994:624-635
Krieger JN, Egan KJ, Ross SO,  et al.  Chronic pelvic pains represent the most prominent urogenital symptoms of “chronic prostatitis.”  Urology. 1996;48(5):715-721
PubMed   |  Link to Article
Alexander RB, Propert KJ, Schaeffer AJ,  et al; Chronic Prostatitis Collaborative Research Network.  Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome.  Ann Intern Med. 2004;141(8):581-589
PubMed   |  Link to Article
Bates SM, Hill VA, Anderson JB,  et al.  A prospective, randomized, double-blind trial to evaluate the role of a short reducing course of oral corticosteroid therapy in the treatment of chronic prostatitis/chronic pelvic pain syndrome.  BJU Int. 2007;99(2):355-359
PubMed   |  Link to Article
Nickel JC. Treatment of chronic prostatitis/chronic pelvic pain syndrome.  Int J Antimicrob Agents. 2008;31:(suppl 1)  S112-S116
PubMed   |  Link to Article
Nickel JC, Narayan P, McKay J, Doyle C. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin.  J Urol. 2004;171(4):1594-1597
PubMed   |  Link to Article
Moreno SG, Sutton AJ, Turner EH,  et al.  Novel methods to deal with publication biases.  BMJ. 2009;339:b2981
PubMed   |  Link to Article
Nüesch E, Trelle S, Reichenbach S,  et al.  Small study effects in meta-analyses of osteoarthritis trials.  BMJ. 2010;341:c3515
PubMed   |  Link to Article
Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons.  Stat Med. 2004;23(20):3105-3124
PubMed   |  Link to Article
Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions.  BMJ. 2003;326(7387):472
PubMed   |  Link to Article
Song F, Harvey I, Lilford R. Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions.  J Clin Epidemiol. 2008;61(5):455-463
PubMed   |  Link to Article
 Stata [computer program]. Release 11. College Station, TX: Stata Corp; 2009
Kaplan SA, Volpe MA, Te AE. A prospective, 1-year trial using saw palmetto vs finasteride in the treatment of category III prostatitis/chronic pelvic pain syndrome.  J Urol. 2004;171(1):284-288
PubMed   |  Link to Article
Kulovac B, Aganović D, Prcić A, Hadziosmanović O. Management of chronic nonbacterial prostatitis/chronic pelvic pain syndrome.  Bosn J Basic Med Sci. 2007;7(3):245-249
PubMed
Cheah PY, Liong ML, Yuen KH,  et al.  Terazosin therapy for chronic prostatitis/chronic pelvic pain syndrome.  J Urol. 2003;169(2):592-596
PubMed   |  Link to Article
Evliyaoğlu Y, Burgut R. Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with α-blocking agent doxazosin; vs placebo.  Int Urol Nephrol. 2002;34(3):351-356
PubMed   |  Link to Article
Gül O, Eroğlu M, Ozok U. Use of terazosine in patients with chronic pelvic pain syndrome and evaluation by Prostatitis Symptom Score Index.  Int Urol Nephrol. 2001;32(3):433-436
PubMed   |  Link to Article
Jeong CW, Lim DJ, Son H,  et al.  Treatment for chronic prostatitis/chronic pelvic pain syndrome: levofloxacin, doxazosin and their combination.  Urol Int. 2008;80(2):157-161
PubMed   |  Link to Article
Leskinen M, Lukkarinen O, Marttila T. Effects of finasteride in patients with inflammatory chronic pelvic pain syndrome.  Urology. 1999;53(3):502-505
PubMed   |  Link to Article
Mehik A, Alas P, Nickel JC,  et al.  Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome.  Urology. 2003;62(3):425-429
PubMed   |  Link to Article
Nickel JC, Downey J, Clark J,  et al.  Levofloxacin for chronic prostatitis/chronic pelvic pain syndrome in men.  Urology. 2003;62(4):614-617
PubMed   |  Link to Article
Nickel JC, Downey J, Pontari MA,  et al.  A randomized placebo-controlled multicentre study to evaluate the safety and efficacy of finasteride for male chronic pelvic pain syndrome (category IIIA chronic nonbacterial prostatitis).  BJU Int. 2004;93(7):991-995
PubMed   |  Link to Article
Nickel JC, Forrest JB, Tomera K,  et al.  Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome.  J Urol. 2005;173(4):1252-1255
PubMed   |  Link to Article
Ye ZQ, Lan RZ, Yang WM,  et al.  Tamsulosin treatment of chronic non-bacterial prostatitis.  J Int Med Res. 2008;36(2):244-252
PubMed   |  Link to Article
Zhao WP, Zhang ZG, Li XD,  et al.  Celecoxib reduces symptoms in men with difficult chronic pelvic pain syndrome (category IIIA).  Braz J Med Biol Res. 2009;42(10):963-967
PubMed   |  Link to Article
Zhou Z, Hong L, Shen X,  et al.  Detection of nanobacteria infection in type III prostatitis.  Urology. 2008;71(6):1091-1095
PubMed   |  Link to Article
Pontari MA, Krieger JN, Litwin MS,  et al; Chronic Prostatitis Collaborative Research Network-2.  Pregabalin for the treatment of men with chronic prostatitis/chronic pelvic pain syndrome.  Arch Intern Med. 2010;170(17):1586-1593
PubMed   |  Link to Article
Shoskes DA, Nickel JC, Dolinga R, Prots D. Clinical phenotyping of patients with chronic prostatitis/chronic pelvic pain syndrome and correlation with symptom severity.  Urology. 2009;73(3):538-542
PubMed   |  Link to Article
Nickel JC, Moon T. Chronic bacterial prostatitis.  Urology. 2005;66(1):2-8
PubMed   |  Link to Article
Nickel JC, Xiang J. Clinical significance of nontraditional bacterial uropathogens in the management of chronic prostatitis.  J Urol. 2008;179(4):1391-1395
PubMed   |  Link to Article
Shoskes DA, Nickel JC, Kattan MW. Phenotypically directed multimodal therapy for chronic prostatitis/chronic pelvic pain syndrome.  Urology. 2010;75(6):1249-1253
PubMed   |  Link to Article
Galley HF, Nelson SJ, Dubbels AM, Webster NR. Effect of ciprofloxacin on the accumulation of interleukin-6, interleukin-8, and nitrite from a human endothelial cell model of sepsis.  Crit Care Med. 1997;25(8):1392-1395
PubMed   |  Link to Article
Yoshimura T, Kurita C, Usami E,  et al.  Immunomodulatory action of levofloxacin on cytokine production by human peripheral blood mononuclear cells.  Chemotherapy. 1996;42(6):459-464
PubMed   |  Link to Article
Katsuno G, Takahashi HK, Iwagaki H,  et al.  The immunosuppressive effects of ciprofloxacin during human mixed lymphocyte reaction.  Clin Immunol. 2006;119(1):110-119
PubMed   |  Link to Article
Nickel JC, Shoskes DA. Phenotypic approach to the management of the chronic prostatitis/chronic pelvic pain syndrome.  BJU Int. 2010;106(9):1252-1263
PubMed   |  Link to Article
Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments.  BMJ. 2005;331(7521):897-900
PubMed   |  Link to Article

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