the management of chronic prostatitis/chronic pelvic pain ... · label represents a heterogeneous...
TRANSCRIPT
The Management of Chronic ProstatitisChronic Pelvic Pain Syndrome
Proposal for a systematic review and network meta-analysis
Thunyarat Anothaisintawee MD
Section for Clinical Epidemiology and Biostatistics Department of Family Medicine Faculty of
Medicine Ramathibodi Hospital Mahidol University Bangkok Thailand
e-mail rattanmahidolacth
John Attia MD PhD FRCPC
Centre for Clinical Epidemiology and Biostatistics School of Medicine and Public Health
University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
e-mail johnattianewcastleeduau
J Curtis Nickel MD FRCSC
Department of Urology Queens University Kingston Ontario Canada
e-mail jcnqueensuca
Sangsuree Thammakraisorn MD
Department of Family Medicine Faculty of Medicine Ramathibodi Hospital Mahidol University
Bangkok Thailand
e-mail rasazmahidolacth
Pawin Numthavaj MD
1
Section for Clinical Epidemiology and Biostatistics Faculty of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
E-mail pawinpawingmailcom
Mark McEvoy MSc
Centre for Clinical Epidemiology and Biostatistics School of Medicine and Public Health
University of New Castle NSW Australia
e-mail markmcevoynewcastleeduau
Ammarin Thakkinstian PhD
Section for Clinical Epidemiology and Biostatistics Faculty of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
e-mail raatkmahidolacth
Corresponding author
Ammarin Thakkinstian Section for Clinical Epidemiology and Biostatistics Ramathibodi Hospital
Rama VI Road Rachatevi Bangkok Thailand 10400 Tel 6622011762 Fax 6622011284
Emailraatkmahidolacth
Word counts 1210
2
INTRODUCTION
ldquoProstatitisrdquo is a common condition with an estimated prevalence in the community of about 91
and accounted for nearly 2 million ambulatory care encounters annually in the US2 However this
label represents a heterogeneous mix of conditions including acute prostatitis chronic bacterial
prostatitis and asymptomatic inflammatory prostatitis with 90-95 of cases being chronic
prostatitischronic pelvic pain syndrome (CPCPPS) 34 CPCPPS is a clinical entity defined as
urologic pain or discomfort in the pelvic region associated with urinary symptoms andor sexual
dysfunction lasting for at least 3 of the previous 6 months These symptoms can diminish not only
quality of life but can also impact physical and psychological function 5 It is a diagnosis of
exclusion and patients should not have active urethritis urogenital cancer urinary tract disease
urethral stricture or neurologic disease affecting the bladder
Although many possible mechanisms have been proposed the etiology of CPCPPS is still
uncertain but may include inflammatory or noninflammatory etiologies6-8 An inciting agent may
cause inflammation or neurological damage in or around the prostate and lead to pelvic floor
neuromuscular dysfunction andor neuropathic pain Factors predisposing individuals to prostatitis
may include genetic predisposition infection voiding abnormalities hormonal imbalance intra-
prostatic reflux immunological or allergic triggers or psychological traits As a result a wide
variety of therapies including α-blockers antibiotics anti-inflammatories and other agents (eg
finasteride phytotherapy and gabapentinoids) are routinely employed However the efficacy of
these treatments is controversial 9-15 partly due to the fact that many of these studies were of small
size with low power to detect treatment effects
To date only one systematic review of α-blockers versus placebo has been performed for the
treatment of CPCPPS 6 Therefore we will perform a systematic review and network meta-
3
analysis mapping all treatment regimens with the following aims first to compare means of total
symptom pain voiding and quality of life scores between α-blocker (the most commonly
evaluated therapy for CPCPPS) and other active drugs or placebo groups second to compare the
rates of response to treatment in these groups
METHODS
Search Strategy
Medline and EMBASE databases will be used for identifying relevant studies published in English
from 1949 (for Medline) or 1974 (for EMBASE) until November 16th 2010 Search terms and
strategies for each database will be described in an Appendix Reference lists of included trials and
previous systematic reviews 6 will also be explored
Selection of studies
Identified studies will be first selected based on their title and abstract by two independent authors
(TA and ST) Full papers will be retrieved if a decision cannot be made from the abstracts
Agreement between the two reviewers will be measured using the kappa statistic Disagreement
will be resolved by consensus and discussion with a third party (AT and JCN)
Inclusion criteria
Randomized controlled studies that were published in English will be selected if they meet with
the following criteria
- Participants with IIIA or IIIB (CPCPPS) categories according to the National
Institutes of Health classification4
- Compared any pair of the following interventions α-blockers antibiotics steroidal amp
non-steroidal anti-inflammatory drugs finasteride glycosminoglycans phytotherapy
gabapentinoids or placebo
4
- Had any of the following outcomes of interest pain scores voiding scores quality of
life scores and total symptom scores (ie a summation of pain voiding and quality of
life scores)
- Full paper can be retrieved and has sufficient data for extraction including number of
patients mean and standard deviation of continuous outcomes in each group andor
numbers of patients per group for dichotomous outcomes
Data extraction
Two authors (TA ST) will independently extract data using a standardized extraction form Any
disagreement will be resolved by discussion or consensus with a third party (AT) Relevant
missing information on the trials will be sought by contacting the corresponding authors of the
studies
Risk of bias assessment
Two authors (TA and PN) will independently assessed risk of bias of each study using an
established tool16 Six domains will be assessed ie sequence generation allocation concealment
blinding incomplete outcome data selective outcome reporting and other sources of bias
Disagreement between the two authors will be resolved by consensus and discussion Levels of
agreement for each domain and the overall domains will be assessed using the Kappa statistic
Outcomes
The outcomes of interest are symptom scores (eg total symptom pain voiding and quality of
life scores) and response rates as defined in the original papers using the following tools
5
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
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Symptoms and Health Status Among Men Urology Apr 199851(4)578-584
7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
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3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
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6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
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8 Hochreiter WW Nadler RB Koch AE et al Evaluation of the cytokines interleukin 8 and
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9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
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of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
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8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
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and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
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199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Section for Clinical Epidemiology and Biostatistics Faculty of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
E-mail pawinpawingmailcom
Mark McEvoy MSc
Centre for Clinical Epidemiology and Biostatistics School of Medicine and Public Health
University of New Castle NSW Australia
e-mail markmcevoynewcastleeduau
Ammarin Thakkinstian PhD
Section for Clinical Epidemiology and Biostatistics Faculty of Medicine Ramathibodi Hospital
Mahidol University Bangkok Thailand
e-mail raatkmahidolacth
Corresponding author
Ammarin Thakkinstian Section for Clinical Epidemiology and Biostatistics Ramathibodi Hospital
Rama VI Road Rachatevi Bangkok Thailand 10400 Tel 6622011762 Fax 6622011284
Emailraatkmahidolacth
Word counts 1210
2
INTRODUCTION
ldquoProstatitisrdquo is a common condition with an estimated prevalence in the community of about 91
and accounted for nearly 2 million ambulatory care encounters annually in the US2 However this
label represents a heterogeneous mix of conditions including acute prostatitis chronic bacterial
prostatitis and asymptomatic inflammatory prostatitis with 90-95 of cases being chronic
prostatitischronic pelvic pain syndrome (CPCPPS) 34 CPCPPS is a clinical entity defined as
urologic pain or discomfort in the pelvic region associated with urinary symptoms andor sexual
dysfunction lasting for at least 3 of the previous 6 months These symptoms can diminish not only
quality of life but can also impact physical and psychological function 5 It is a diagnosis of
exclusion and patients should not have active urethritis urogenital cancer urinary tract disease
urethral stricture or neurologic disease affecting the bladder
Although many possible mechanisms have been proposed the etiology of CPCPPS is still
uncertain but may include inflammatory or noninflammatory etiologies6-8 An inciting agent may
cause inflammation or neurological damage in or around the prostate and lead to pelvic floor
neuromuscular dysfunction andor neuropathic pain Factors predisposing individuals to prostatitis
may include genetic predisposition infection voiding abnormalities hormonal imbalance intra-
prostatic reflux immunological or allergic triggers or psychological traits As a result a wide
variety of therapies including α-blockers antibiotics anti-inflammatories and other agents (eg
finasteride phytotherapy and gabapentinoids) are routinely employed However the efficacy of
these treatments is controversial 9-15 partly due to the fact that many of these studies were of small
size with low power to detect treatment effects
To date only one systematic review of α-blockers versus placebo has been performed for the
treatment of CPCPPS 6 Therefore we will perform a systematic review and network meta-
3
analysis mapping all treatment regimens with the following aims first to compare means of total
symptom pain voiding and quality of life scores between α-blocker (the most commonly
evaluated therapy for CPCPPS) and other active drugs or placebo groups second to compare the
rates of response to treatment in these groups
METHODS
Search Strategy
Medline and EMBASE databases will be used for identifying relevant studies published in English
from 1949 (for Medline) or 1974 (for EMBASE) until November 16th 2010 Search terms and
strategies for each database will be described in an Appendix Reference lists of included trials and
previous systematic reviews 6 will also be explored
Selection of studies
Identified studies will be first selected based on their title and abstract by two independent authors
(TA and ST) Full papers will be retrieved if a decision cannot be made from the abstracts
Agreement between the two reviewers will be measured using the kappa statistic Disagreement
will be resolved by consensus and discussion with a third party (AT and JCN)
Inclusion criteria
Randomized controlled studies that were published in English will be selected if they meet with
the following criteria
- Participants with IIIA or IIIB (CPCPPS) categories according to the National
Institutes of Health classification4
- Compared any pair of the following interventions α-blockers antibiotics steroidal amp
non-steroidal anti-inflammatory drugs finasteride glycosminoglycans phytotherapy
gabapentinoids or placebo
4
- Had any of the following outcomes of interest pain scores voiding scores quality of
life scores and total symptom scores (ie a summation of pain voiding and quality of
life scores)
- Full paper can be retrieved and has sufficient data for extraction including number of
patients mean and standard deviation of continuous outcomes in each group andor
numbers of patients per group for dichotomous outcomes
Data extraction
Two authors (TA ST) will independently extract data using a standardized extraction form Any
disagreement will be resolved by discussion or consensus with a third party (AT) Relevant
missing information on the trials will be sought by contacting the corresponding authors of the
studies
Risk of bias assessment
Two authors (TA and PN) will independently assessed risk of bias of each study using an
established tool16 Six domains will be assessed ie sequence generation allocation concealment
blinding incomplete outcome data selective outcome reporting and other sources of bias
Disagreement between the two authors will be resolved by consensus and discussion Levels of
agreement for each domain and the overall domains will be assessed using the Kappa statistic
Outcomes
The outcomes of interest are symptom scores (eg total symptom pain voiding and quality of
life scores) and response rates as defined in the original papers using the following tools
5
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
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a physician-assigned diagnosis of prostatitis the Olmsted County Study of Urinary
Symptoms and Health Status Among Men Urology Apr 199851(4)578-584
7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
INTRODUCTION
ldquoProstatitisrdquo is a common condition with an estimated prevalence in the community of about 91
and accounted for nearly 2 million ambulatory care encounters annually in the US2 However this
label represents a heterogeneous mix of conditions including acute prostatitis chronic bacterial
prostatitis and asymptomatic inflammatory prostatitis with 90-95 of cases being chronic
prostatitischronic pelvic pain syndrome (CPCPPS) 34 CPCPPS is a clinical entity defined as
urologic pain or discomfort in the pelvic region associated with urinary symptoms andor sexual
dysfunction lasting for at least 3 of the previous 6 months These symptoms can diminish not only
quality of life but can also impact physical and psychological function 5 It is a diagnosis of
exclusion and patients should not have active urethritis urogenital cancer urinary tract disease
urethral stricture or neurologic disease affecting the bladder
Although many possible mechanisms have been proposed the etiology of CPCPPS is still
uncertain but may include inflammatory or noninflammatory etiologies6-8 An inciting agent may
cause inflammation or neurological damage in or around the prostate and lead to pelvic floor
neuromuscular dysfunction andor neuropathic pain Factors predisposing individuals to prostatitis
may include genetic predisposition infection voiding abnormalities hormonal imbalance intra-
prostatic reflux immunological or allergic triggers or psychological traits As a result a wide
variety of therapies including α-blockers antibiotics anti-inflammatories and other agents (eg
finasteride phytotherapy and gabapentinoids) are routinely employed However the efficacy of
these treatments is controversial 9-15 partly due to the fact that many of these studies were of small
size with low power to detect treatment effects
To date only one systematic review of α-blockers versus placebo has been performed for the
treatment of CPCPPS 6 Therefore we will perform a systematic review and network meta-
3
analysis mapping all treatment regimens with the following aims first to compare means of total
symptom pain voiding and quality of life scores between α-blocker (the most commonly
evaluated therapy for CPCPPS) and other active drugs or placebo groups second to compare the
rates of response to treatment in these groups
METHODS
Search Strategy
Medline and EMBASE databases will be used for identifying relevant studies published in English
from 1949 (for Medline) or 1974 (for EMBASE) until November 16th 2010 Search terms and
strategies for each database will be described in an Appendix Reference lists of included trials and
previous systematic reviews 6 will also be explored
Selection of studies
Identified studies will be first selected based on their title and abstract by two independent authors
(TA and ST) Full papers will be retrieved if a decision cannot be made from the abstracts
Agreement between the two reviewers will be measured using the kappa statistic Disagreement
will be resolved by consensus and discussion with a third party (AT and JCN)
Inclusion criteria
Randomized controlled studies that were published in English will be selected if they meet with
the following criteria
- Participants with IIIA or IIIB (CPCPPS) categories according to the National
Institutes of Health classification4
- Compared any pair of the following interventions α-blockers antibiotics steroidal amp
non-steroidal anti-inflammatory drugs finasteride glycosminoglycans phytotherapy
gabapentinoids or placebo
4
- Had any of the following outcomes of interest pain scores voiding scores quality of
life scores and total symptom scores (ie a summation of pain voiding and quality of
life scores)
- Full paper can be retrieved and has sufficient data for extraction including number of
patients mean and standard deviation of continuous outcomes in each group andor
numbers of patients per group for dichotomous outcomes
Data extraction
Two authors (TA ST) will independently extract data using a standardized extraction form Any
disagreement will be resolved by discussion or consensus with a third party (AT) Relevant
missing information on the trials will be sought by contacting the corresponding authors of the
studies
Risk of bias assessment
Two authors (TA and PN) will independently assessed risk of bias of each study using an
established tool16 Six domains will be assessed ie sequence generation allocation concealment
blinding incomplete outcome data selective outcome reporting and other sources of bias
Disagreement between the two authors will be resolved by consensus and discussion Levels of
agreement for each domain and the overall domains will be assessed using the Kappa statistic
Outcomes
The outcomes of interest are symptom scores (eg total symptom pain voiding and quality of
life scores) and response rates as defined in the original papers using the following tools
5
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
References 1 Roberts RO Lieber MM Rhodes T Girman CJ Bostwick DG Jacobsen SJ Prevalence of
a physician-assigned diagnosis of prostatitis the Olmsted County Study of Urinary
Symptoms and Health Status Among Men Urology Apr 199851(4)578-584
7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
analysis mapping all treatment regimens with the following aims first to compare means of total
symptom pain voiding and quality of life scores between α-blocker (the most commonly
evaluated therapy for CPCPPS) and other active drugs or placebo groups second to compare the
rates of response to treatment in these groups
METHODS
Search Strategy
Medline and EMBASE databases will be used for identifying relevant studies published in English
from 1949 (for Medline) or 1974 (for EMBASE) until November 16th 2010 Search terms and
strategies for each database will be described in an Appendix Reference lists of included trials and
previous systematic reviews 6 will also be explored
Selection of studies
Identified studies will be first selected based on their title and abstract by two independent authors
(TA and ST) Full papers will be retrieved if a decision cannot be made from the abstracts
Agreement between the two reviewers will be measured using the kappa statistic Disagreement
will be resolved by consensus and discussion with a third party (AT and JCN)
Inclusion criteria
Randomized controlled studies that were published in English will be selected if they meet with
the following criteria
- Participants with IIIA or IIIB (CPCPPS) categories according to the National
Institutes of Health classification4
- Compared any pair of the following interventions α-blockers antibiotics steroidal amp
non-steroidal anti-inflammatory drugs finasteride glycosminoglycans phytotherapy
gabapentinoids or placebo
4
- Had any of the following outcomes of interest pain scores voiding scores quality of
life scores and total symptom scores (ie a summation of pain voiding and quality of
life scores)
- Full paper can be retrieved and has sufficient data for extraction including number of
patients mean and standard deviation of continuous outcomes in each group andor
numbers of patients per group for dichotomous outcomes
Data extraction
Two authors (TA ST) will independently extract data using a standardized extraction form Any
disagreement will be resolved by discussion or consensus with a third party (AT) Relevant
missing information on the trials will be sought by contacting the corresponding authors of the
studies
Risk of bias assessment
Two authors (TA and PN) will independently assessed risk of bias of each study using an
established tool16 Six domains will be assessed ie sequence generation allocation concealment
blinding incomplete outcome data selective outcome reporting and other sources of bias
Disagreement between the two authors will be resolved by consensus and discussion Levels of
agreement for each domain and the overall domains will be assessed using the Kappa statistic
Outcomes
The outcomes of interest are symptom scores (eg total symptom pain voiding and quality of
life scores) and response rates as defined in the original papers using the following tools
5
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
References 1 Roberts RO Lieber MM Rhodes T Girman CJ Bostwick DG Jacobsen SJ Prevalence of
a physician-assigned diagnosis of prostatitis the Olmsted County Study of Urinary
Symptoms and Health Status Among Men Urology Apr 199851(4)578-584
7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
- Had any of the following outcomes of interest pain scores voiding scores quality of
life scores and total symptom scores (ie a summation of pain voiding and quality of
life scores)
- Full paper can be retrieved and has sufficient data for extraction including number of
patients mean and standard deviation of continuous outcomes in each group andor
numbers of patients per group for dichotomous outcomes
Data extraction
Two authors (TA ST) will independently extract data using a standardized extraction form Any
disagreement will be resolved by discussion or consensus with a third party (AT) Relevant
missing information on the trials will be sought by contacting the corresponding authors of the
studies
Risk of bias assessment
Two authors (TA and PN) will independently assessed risk of bias of each study using an
established tool16 Six domains will be assessed ie sequence generation allocation concealment
blinding incomplete outcome data selective outcome reporting and other sources of bias
Disagreement between the two authors will be resolved by consensus and discussion Levels of
agreement for each domain and the overall domains will be assessed using the Kappa statistic
Outcomes
The outcomes of interest are symptom scores (eg total symptom pain voiding and quality of
life scores) and response rates as defined in the original papers using the following tools
5
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
References 1 Roberts RO Lieber MM Rhodes T Girman CJ Bostwick DG Jacobsen SJ Prevalence of
a physician-assigned diagnosis of prostatitis the Olmsted County Study of Urinary
Symptoms and Health Status Among Men Urology Apr 199851(4)578-584
7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
- NIH chronic prostatitis symptom index (NIH-CPSI) consisting of three domains (ie
pain voiding and quality of life) The overall total scores range from 0 to 4317
- International prostate symptom score (IPSS ) questionnaire18 consisting of three
domains (ie voiding pain and quality of life) with combined total scores which
range from 0 to 51
- Prostatitis symptom score index (PSSI) measuring only pain scores with a total score
range from 0 to 12
- Pain and voiding questionnaires19 which consists of 7 and 5 items respectively grading
each item from 0 to 3
For all of these measurements scores close to 0 reflect more favourable status The minimal
clinical significant difference for all these scales is in the range from 3 to 6 points20-23 For
response to treatment various definitions will be used as in the original studies eg 25 33 or
50 decreases in NIH-CPSI or 4 (clinically perceptible improvement) - 6 (clinically significant
improvement) unit score decreases in NIH-CPSI from baseline
Statistical Analysis
For direct meta-analysis the mean differences of continuous outcomes (ie total score pain
voiding and quality of life scores) between treatment groups will be estimated for each study and
pooled using a standardized mean difference (SMD) if the scale used for measurements is
different otherwise an unstandardized mean difference (USMD) will be applied Heterogeneity of
the mean difference will be assessed using Q and I2 statistics If heterogeneity is present or the
degree of heterogeneity I2 is gt 25 the SMD will be estimated using a random effects model
otherwise a fixed effects model will be applied
6
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
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33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
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34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
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200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
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37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
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International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
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Urology Jun 200871(6)1091-1095
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Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
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45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
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Mar 200973(3)538-542 discussion 542-533
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200566(1)2-8
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management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
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chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Relative risk (RR) of response to treatment will be estimated for each study If there is evidence of
heterogeneity a random effects model will be used for pooling otherwise the inverse-variance
method will be used The source of heterogeneity will be explored by fitting co-variables (ie
mean age duration of treatment and baseline total symptom scores) one by one in the meta-
regression Publication bias will be assessed using contour enhanced funnel plots and Eggerrsquos test
24 25
For indirect comparisons network meta-analysis will be applied to assess treatment effects for all
possible treatment arms if summary data is available 26-28 Linear regression models weighted by
inverse variance will be applied to assess treatment effects for continuous outcomes and study
variables will be included as covariates in the model For response to treatment summary data
will be expanded to individual patient level data using the expand command in STATA Treatment
groups will be considered in a mixed effect hierarchical model with a log-link function using the
xtpoisson command26 The pooled RRs and 95 confidence interval (CI) will be estimated by
exponential coefficients of treatments All analyses will be performed using STATA version
11029 P values with two-sided tests lt 005 will be considered statistically significant except for
the heterogeneity test where one-sided p lt010 will be used
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7
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
2 Collins MM Stafford RS OLeary MP Barry MJ How common is prostatitis A national
survey of physician visits J Urol Apr 1998159(4)1224-1228
3 de la Rosette JJ Hubregtse MR Meuleman EJ Stolk-Engelaar MV Debruyne FM
Diagnosis and treatment of 409 patients with prostatitis syndromes Urology Apr
199341(4)301-307
4 Krieger JN Nyberg L Jr Nickel JC NIH consensus definition and classification of
prostatitis JAMA Jul 21 1999282(3)236-237
5 McNaughton Collins M Pontari MA OLeary MP et al Quality of life is impaired in men
with chronic prostatitis the Chronic Prostatitis Collaborative Research Network Journal of
general internal medicine Oct 200116(10)656-662
6 McNaughton Collins M MacDonald R Wilt TJ Diagnosis and treatment of chronic
abacterial prostatitis a systematic review Ann Intern Med Sep 5 2000133(5)367-381
7 Hetrick DC Ciol MA Rothman I Turner JA Frest M Berger RE Musculoskeletal
dysfunction in men with chronic pelvic pain syndrome type III a case-control study J
Urol Sep 2003170(3)828-831
8 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 Dec 20 200056(6)1025-1029
9 Nickel JC Krieger JN McNaughton-Collins M et al Alfuzosin and symptoms of chronic
prostatitis-chronic pelvic pain syndrome N Engl J Med Dec 18 2008359(25)2663-2673
10 Tugcu V Tasci AI Fazlioglu A et al A Placebo-Controlled Comparison of the Efficiency
of Triple- and Monotherapy in Category III B Chronic Pelvic Pain Syndrome (CPPS)
European Urology 200751(4)1113-1118
8
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
11 Goldmeier D Madden P McKenna M Tamm N Treatment of category III A prostatitis
with zafirlukast A randomized controlled feasibility study International Journal of STD
and AIDS 200516(3)196-200
12 Nickel JC Pontari M Moon T et al A randomized placebo controlled multicenter study
to evaluate the safety and efficacy of rofecoxib in the treatment of chronic nonbacterial
prostatitis Journal of Urology 2003169(4)1401-1405
13 Elist J Effects of pollen extract preparation ProstatPoltit on lower urinary tract symptoms
in patients with chronic nonbacterial prostatitischronic pelvic pain syndrome a
randomized double-blind placebo-controlled study Urology Jan 200667(1)60-63
14 Shoskes DA Zeitlin SI Shahed A Rajfer J Quercetin in men with category III chronic
prostatitis a preliminary prospective double-blind placebo-controlled trial Urology Dec
199954(6)960-963
15 Wagenlehner FM Schneider H Ludwig M Schnitker J Brahler E Weidner W A pollen
extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain
syndrome a multicentre randomised prospective double-blind placebo-controlled phase
3 study Eur Urol Sep 200956(3)544-551
16 Higgins JPT ADe Assessing risk of bias in included studies Cochrane Handbook for
Systematic Reviews of Interventions [wwwcochrane-handbookorg] 2008 501 2008
17 Litwin MS McNaughton-Collins M Fowler FJ Jr et al The National Institutes of Health
chronic prostatitis symptom index development and validation of a new outcome measure
Chronic Prostatitis Collaborative Research Network J Urol Aug 1999162(2)369-375
18 Cockett ATK KS Aso Y et al The Second International Consultation on Benign Prostatic
Hyperplasia Scientific Communication International Channel Island1994624-635
9
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
19 Krieger JN Egan KJ Ross SO Jacobs R Berger RE Chronic pelvic pains represent the
most prominent urogenital symptoms of chronic prostatitis Urology Nov
199648(5)715-721 discussion 721-712
20 Alexander RB Propert KJ Schaeffer AJ et al Ciprofloxacin or tamsulosin in men with
chronic prostatitischronic pelvic pain syndrome a randomized double-blind trial Ann
Intern Med Oct 19 2004141(8)581-589
21 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 prostatitischronic pelvic pain syndrome BJU International 200799(2)355-359
22 Nickel JC Treatment of chronic prostatitischronic pelvic pain syndrome International
Journal of Antimicrobial Agents 200831(Supplement 1)112-116
23 Nickel JC Narayan P McKay J Doyle C Treatment of chronic prostatitischronic pelvic
pain syndrome with tamsulosin A randomized double blind trial Journal of Urology
2004171(4)1594-1597
24 Moreno SG Sutton AJ Turner EH et al Novel methods to deal with publication biases
secondary analysis of antidepressant trials in the FDA trial registry database and related
journal publications BMJ (Clinical research ed 2009339b2981
25 Nuesch E Trelle S Reichenbach S et al Small study effects in meta-analyses of
osteoarthritis trials meta-epidemiological study BMJ (Clinical research ed341c3515
26 Lu G Ades AE Combination of direct and indirect evidence in mixed treatment
comparisons Stat Med Oct 30 200423(20)3105-3124
27 Song F Altman DG Glenny AM Deeks JJ Validity of indirect comparison for estimating
efficacy of competing interventions empirical evidence from published meta-analyses
BMJ (Clinical research ed Mar 1 2003326(7387)472
10
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
28 Song F Harvey I Lilford R Adjusted indirect comparison may be less biased than direct
comparison for evaluating new pharmaceutical interventions J Clin Epidemiol May
200861(5)455-463
29 Stata Release 11 Statistical Software [computer program] Version Release 11 College
Station TX StataCorp LP 2009
30 Kaplan SA Volpe MA Te AE A prospective 1-year trial using saw palmetto versus
finasteride in the treatment of category III prostatitischronic pelvic pain syndrome Journal
of Urology 2004171(1)284-288
31 Kulovac B Aganovic D Prcic A Hadziosmanovic O Management of chronic nonbacterial
prostatitischronic pelvic pain syndrome Bosn J Basic Med Sci Aug 20077(3)245-249
32 Cheah PY Liong ML Yuen KH et al Terazosin therapy for chronic prostatitischronic
pelvic pain syndrome A randomized placebo controlled trial Journal of Urology
2003169(2)592-596
33 Evliyaoglu Y Burgut R Lower urinary tract symptoms pain and quality of life assessment
in chronic non-bacterial prostatitis patients treated with (alpha)-blocking agent doxazosin
Versus placebo International Urology and Nephrology 200234(3)351-356
34 Gul O Eroglu M Ozok U Use of terazosine in patients with chronic pelvic pain syndrome
and evaluation by prostatitis symptom score index International Urology and Nephrology
200132(3)433-436
35 Jeong CW Lim DJ Son H Lee SE Jeong H Treatment for chronic prostatitischronic
pelvic pain syndrome Levofloxacin doxazosin and their combination Urologia
Internationalis 200880(2)157-161
36 Leskinen M Lukkarinen O Marttila T Effects of finasteride in patients with inflammatory
chronic pelvic pain syndrome A double-blind placebo-controlled pilot study Urology
199953(3)502-505
11
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
37 Mehik A Alas P Nickel JC Sarpola A Helstrom PJ Alfuzosin treatment for chronic
prostatitischronic pelvic pain syndrome A prospective randomized double-blind
placebo-controlled pilot study Urology 200362(3)425-429
38 Nickel JC Downey J Clark J et al Levofloxacin for chronic prostatitischronic pelvic pain
syndrome in men A randomized placebo-controlled multicenter trial Urology
200362(4)614-617
39 Nickel JC Downey J Pontari MA Shoskes DA Zeitlin SI 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
International 200493(7)991-995
40 Nickel JC Forrest JB Tomera K et al Pentosan polysulfate sodium therapy for men with
chronic pelvic pain syndrome a multicenter randomized placebo controlled study J Urol
Apr 2005173(4)1252-1255
41 Ye ZQ Lan RZ Yang WM Yao LF Yu X Tamsulosin treatment of chronic non-bacterial
prostatitis Journal of International Medical Research 200836(2)244-252
42 Zhao WP Zhang ZG Li XD et al Celecoxib reduces symptoms in men with difficult
chronic pelvic pain syndrome (Category IIIA) Brazilian Journal of Medical and Biological
Research 200942(10)963-967
43 Zhou Z Hong L Shen X et al Detection of nanobacteria infection in type III prostatitis
Urology Jun 200871(6)1091-1095
44 Pontari MA Krieger JN Litwin MS et al Pregabalin for the Treatment of Men With
Chronic ProstatitisChronic Pelvic Pain Syndrome A Randomized Controlled Trial Arch
Intern Med September 20101701586-1593
12
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
45 Shoskes DA Nickel JC Dolinga R Prots D Clinical phenotyping of patients with chronic
prostatitischronic pelvic pain syndrome and correlation with symptom severity Urology
Mar 200973(3)538-542 discussion 542-533
46 Nickel JC Moon T Chronic bacterial prostatitis an evolving clinical enigma Urology Jul
200566(1)2-8
47 Nickel JC Xiang J Clinical significance of nontraditional bacterial uropathogens in the
management of chronic prostatitis J Urol Apr 2008179(4)1391-1395
48 Shoskes DA Nickel JC Kattan MW Phenotypically directed multimodal therapy for
chronic prostatitischronic pelvic pain syndrome a prospective study using UPOINT
Urology Jun 201075(6)1249-1253
49 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 Aug 199725(8)1392-1395
50 Yoshimura T Kurita C Usami E et al Immunomodulatory action of levofloxacin on
cytokine production by human peripheral blood mononuclear cells Chemotherapy Nov-
Dec 199642(6)459-464
51 Katsuno G Takahashi HK Iwagaki H et al The immunosuppressive effects of
ciprofloxacin during human mixed lymphocyte reaction Clin Immunol Apr
2006119(1)110-119
52 Nickel JC Shoskes D Phenotypic Approach to the management of the Chronic
ProstatitisChronic Pelvic Pain Syndrome BJU Int 2010in press
53 Lee SW Liong ML Yuen KH Liong YV Krieger JN Chronic prostatitischronic pelvic
pain syndrome role of alpha blocker therapy Urol Int 200778(2)97-105
54 Murphy AB Macejko A Taylor A Nadler RB Chronic prostatitis management strategies
Drugs 200969(1)71-84
13
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
55 Yang G Wei Q Li H Yang Y Zhang S Dong Q The effect of alpha-adrenergic
antagonists in chronic prostatitischronic pelvic pain syndrome a meta-analysis of
randomized controlled trials J Androl Nov-Dec 200627(6)847-852
56 Caldwell DM Ades AE Higgins JP Simultaneous comparison of multiple treatments
combining direct and indirect evidence BMJ (Clinical research ed Oct 15 2005
331(7521)897-900
14
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Figure legends
Figure 1 Flow chart of selecting studies
Figure 2 Contour enhanced funnel plot
A) Total score between α-blocker and placebo groups
B) Pain
C) Void
D) QoL
A)
15
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Table 1 Characteristics of included studies
Author Intervention No of subjects
Duration of treatment (weeks)
Outcome measurement
Mea
α-blocker vs placebo
Nickel JC9 2008 Alfuzosin 138 12 NIH-CPSI 40 Placebo 134 Tugcu V10 2007 Doxazosin 30 24 NIH-CPSI 29 Placebo 30 Alexander RB20 2004 Ciprofloxacin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC23 2004 Tamsulosin 27 6 NIH-CPSI 40 Placebo 30 Cheah PY32 2003 Terazosin 43 14 NIH-CPSI 35 Placebo 43 Evliyaoglu Y33 2002 Doxazosin 30 12 IPSS pain score 3 Placebo 30 Gul O34 2001 Terazosine 39 12 PSSI 3 Placebo 30 Mehik A37 2003 Alfuzosin 19 24 NIH-CPSI 4 Placebo 21 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Antibiotic vs placebo
Alexander RB20 2004 Tamsulosin 49 6 NIH-CPSI 44 Placebo 49 Nickel JC38 2003 Levofloxacin 45 6 NIH-CPSI 56 Placebo 35 Zhou Z43 2008 Tetracycline HCL 24 12 NIH-CPSI Placebo 24 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Finasteride VS placebo
Leskinen M36 1999 Finasteride 31 52 IPSS pain score 46 Placebo 10 Nickel JC39 2004 Finasteride 33 24 NIH-CPSI 44 Placebo 31 Author Intervention No of
subjects Duration of treatment (weeks)
Outcome measurement
Mea
Anti-inflammatory vs placebo
Goldmeier D11 2005 Zafirlukast 10 4 NIH-CPSI 35 Placebo 7 Nickel JC12 2003 Rofecoxib 49 6 NIH-CPSI 46 Placebo 59 Bates SM21 2007 Prednisolone 9 4 NIH-CPSI 40
16
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Placebo 12 Zhao WP42 2009 Celecoxib 32 6 NIH-CPSI Placebo 32 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Phytotherapy VS placebo
Elist J13 2006 ProstatPoltit 30 24 Questionnaire 35 Placebo 30 Shoskes DA14 1999 Quercetin 15 4 NIH-CPSI 44 Placebo 15 Wagenlehner F15 2009 Cernilton 70 12 NIH-CPSI 39 Placebo 69 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Glycosaminoglycan VS placebo
Nickel JC40 2005 Pentosan polysulfate 51 16 NIH-CPSI 392 Placebo 49 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Pregabalin VS placebo
Potari MA44 2010 Pregabalin 217 6 NIH-CPSI Placebo 104 Author Intervention No of
subjects
Duration of treatment (weeks)
Outcome measurement
Mea
Dual VS mono-therapies
Alexander RB20 2004 Ciprofloxacin+tamsulosin 49 6 NIH-CPSI 44 Tamsulosin 49 Ciprofloxacin 49 Placebo 49 Jeong CW35 2008 Doxazosin + levofloxacin 29 6 NIH-CPSI 40 Doxazosin 26 Levofloxacin 26 Ye ZQ41 2008 Tamsulosin +
levofloxacin 42 12 NIH-CPSI
Tamsulosin 42 levofloxacin 21
a Measured at baseline before receiving treatments b range Table 2 Mean symptom scores between α-blockers and placebo groups
Author Outcome measurement
A Total score α-blockers Placebo
Na
Mean SD N Mean SD
Nickel JC9 NIH-CPSI 138 167 149 134 186 141 Tugcu V10 NIH-CPSI 30 107 13 30 219 12 Alexander RB20 NIH-CPSI 45 202 122 45 216 98
17
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Cheah PY32 NIH-CPSI 43 108 90 43 170 121 Evliyaoglu Y33 IPSS and pain
questionnaire 30 105 44 30 162 57
SMD 95 CI -17 -28 -06 Antibiotics Placebo N mean SD N Mean SD Alexander RB20 NIH-CPSI 42 180 132 45 216 98 Nickel JC38 NIH-CPSI 45 190 95 35 184 91 Zhou Z43 NIH-CPSI 24 171 28 24 31 25 USMD 95 CI -58 -159 44
Author Outcome measurement
B Pain score α-blockers Placebo
N mean SD N Mean SD Nickel JC9 NIH-CPSI 138 78 76 134 85 76 Tugcu V10 NIH-CPSI 30 47 12 30 86 08 Alexander RB20 NIH-CPSI 45 90 71 45 106 58 Cheah PY32 NIH-CPSI 43 52 57 43 78 67 Evliyaoglu Y33 Pain
questionnaire 30 23 11 30 37 13
Gul O34 PSSI 39 63 16 30 88 27 SMD 95 CI -11 -18 -03 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 87 67 45 106 58 Nickel JC38 NIH-CPSI 45 89 50 35 76 47 Zhou Z43 NIH-CPSI 24 71 10 24 145 20 USMD 95 CI -27 -87 32 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 28 33 28 49 38
Shoskes DA14 NIH-CPSI 15 62 39 13 90 32 Wagenlehner F15 NIH-CPSI 68 55 49 68 73 49 SMD 95 CI -05 -07 -02
Author Outcome measurement
C Voiding score α-blockers Placebo
N mean SD N mean SD Nickel JC9 NIH-CPSI 138 33 40 134 39 41 Tugcu V10 NIH-CPSI 30 22 08 30 64 10 Alexander RB20 NIH-CPSI 45 42 40 45 106 58 Cheah PY32 NIH-CPSI 43 20 28 43 36 36 Evliyaoglu Y33 IPSS 30 59 25 30 88 36 SMD 95 CI -14 -23 -05 Antibiotics Placebo N mean SD N mean SD Alexander RB20 NIH-CPSI 42 35 38 45 106 58 Nickel JC38 NIH-CPSI 45 42 30 35 41 28
18
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Zhou Z43 NIH-CPSI 24 5 08 24 8 05 USMD 95 CI -32 -61 -03 Author Outcome
measurement Phytotherapy Placebo
N mean SD N mean SD Elist J13 Pain
questionnaire 30 14 21 28 28 28
Shoskes DA14 NIH-CPSI 15 15 19 13 30 27 Wagenlehner F15 NIH-CPSI 68 18 29 69 26 31 SMD 95 CI -04 -07 -01 Author Outcome
measurement D QoL score
α-blockers Placebo N mean SD N mean SD
Nickel JC9 NIH-CPSI 138 33 25 134 35 23 Tugcu V10 NIH-CPSI 30 38 11 30 69 11 Alexander RB20 NIH-CPSI 45 69 34 45 71 33 Cheah PY32 NIH-CPSI 43 36 34 43 55 39 Evliyaoglu Y33 IPSS 30 23 08 30 37 08 SMD 95 CI -10 -18 -02 Author Outcome
measurement Antibiotics Placebo
N mean SD N mean SD Alexander RB20 NIH-CPSI 42 58 39 45 71 33 Nickel JC38 NIH-CPSI 45 37 18 35 38 17 Zhou Z43 NIH-CPSI 24 55 06 24 85 10 USMD 95 CI -15 -36 06 aNumber of subjects
19
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Table 3 Treatment response and treatment effects between α-blockers anti-inflammatory and placebo groups
Author Definitiona α-blockers Placebo RR 95 CI No of
response No of non-
response No of
response No of non-
response Nickel JC9 4 points decrease
in NIH-CPSI 68 70 66 68 10 08 13
Tugcu V10 50 decrease in NIH-CPSI
20 10 10 20 20 14 35
Alexander RB20 4 points decrease in NIH-CPSI
12 33 11 34 11 05 23
Nickel JC23 50 decrease in NIH-CPSI
9 18 5 25 20 08 52
Cheah PY32 50 decrease in NIH-CPSI
24 19 14 29 16 10 26
Mehik A37 33 decrease in NIH-CPSI
13 4 4 16 25 14 45
Pooled RR 16 11 23 Author Definitiona Anti-inflammatory Placebo RR 95 CI
No of response
No of non- response
No of response
No of non- response
Nickel JC12 25 decrease in NIH-CPSI
31 18 24 35 16 11 26
Bates SM21 6 points decrease in NIH-CPSI
2 4 4 8 10 03 40
Zhao WP42 25 decrease in NIH-CPSI
25 7 10 22 25 15 43
Pooled RR 18 12 26 adefinition of response to treatment
20
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
Appendix Search strategies
EMBASE
1 antibioticexp OR antibiotic
2 alpha blocker
3 alpha adrenergic receptor blocker
4 alpha adrenergic receptor antagonist
5 alpha adrenergic blocker
6 alpha adrenergic antagonist
7 chronic pelvic pain
8 chronic prostatitis
9 antibacterial
10 quinoloneexp OR quinolone
11 nonsteroidal antiinflammatory
12 cyclooxygenase-2 inhibitorexp OR cyclooxygenase-2 inhibitor
13 corticosteroidexp OR corticosteroid
14 finasterideexp OR finasteride
15 glycosaminoglycanexp OR glycosaminoglycan
21
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
16 phytotherapyexp OR phytotherapy
17 pregabalin
18 7 OR 8
19 2 OR 3 OR 4 OR 5 OR 6
20 1 OR 9 OR 10
21 11 OR 12 OR 13
22 14 OR 15 OR 16 OR 17
23 19 OR 20 OR 21 OR 22
24 18 AND 23
25 randomized controlled trialexp OR randomized controlled trial OR randomised controlled trialexp OR randomised
26 24 AND 25
Medline
((chronic pelvic pain) OR (chronic prostatitis)) AND (((alpha adrenergic AND blocker) OR (alpha adrenergic AND antagonist) OR
(adrenergic alpha antagonist)) OR ((antibiotics) OR (antibacterial) OR (quinolones)) OR (((non-steroidal anti-inflammatory) OR
(nonsteroidal anti-inflammatory) OR (cyclooxygenase-2 inhibitor)) OR (corticosteroid)) OR ((finasteride) OR (glycosaminoglycan)
OR (phytotherapy) OR (pregabalin)))
22
23
23