Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome.

Background

Description of the condition

Prostatitis is a common disorder affecting 10% to 14% of men in Europe and the USA (Bajpayee 2012). This health problem motivates one per cent of primary care visits and eight per cent of urology consultations in the USA (Collins 1998). Only five to 10 per cent of prostatitis cases have a bacterial origin (Bartoletti 2007; De La Rosette 1993). This disorder can affect men of all ages and ethnic origins, but it is more common in younger men with a mean age of onset at 42 years old (Schaeffer 2002). The two main clinical features of prostatitis are pelvic pain and lower urinary tract symptoms, even though there is a wide range of clinical presentations (Nickel 1999).

The National Institutes of Health (NIH) classification identifies four types of prostatitis (Nickel 1999): types I and II, being acute and chronic bacterial prostatitis respectively; type III, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS); and type IV, asymptomatic prostatitis. It remains unclear whether type III can be linked in all cases to prostatic involvement (True 1999), thus the alternate denomination (Chronic Pelvic Pain Syndrome). CP/CPPS is sub‐classified as type IIIa, inflammatory, and type IIIb, noninflammatory, depending on the presence of inflammatory cells in prostatic secretions.

CP/CPPS is defined when pelvic pain is present for at least three of the preceding six months and no other identifiable causes have been detected (Nickel 1999). Other symptoms include obstructive or irritative voiding difficulties, ejaculatory pain, and hematospermia. Men affected by CP/CPPS have a significantly decreased quality of life and the level of pelvic pain is strongly associated with sexual dysfunction (Trinchieri 2007; Walz 2007). CP/CPPS is associated with other functional somatic syndromes such as irritable bowel syndrome, interstitial cystitis, chronic fatigue syndrome and fibromyalgia (Rodriguez 2009; Suskind 2013). Diagnosis is usually based on patient history, physical examination, urinalysis and 2‐ or 4‐glass test (Nickel 2012). Further investigations are performed when considering differential diagnosis.

There are different theories regarding the aetiology and pathophysiology of CP/CPPS, as follows.

• Infection: bacterial DNA is detected in a significant proportion of men with CP/CPPS (Hou 2012). A previous history of sexually transmitted infection is more frequent in men with CP/CPPS (Pontari 2005). Nevertheless, the isolation of uropathogenic bacteria in prostatic fluids is similar to controls (Nickel 2003a).

• Inflammation/autoimmunity: elevated concentrations of proinflammatory cytokines (interleukin 1, tumor necrosis factor, interferon‐γ) and of autoimmunity activity (T‐cell proliferation responses to prostate antigens) is found in men suffering from CP/CPPS and in animal models (Pontari 2004).

• Neuropsychological factors: the central nervous system might be involved through several mechanisms of pain sensitisation (Miller 2002; Yang 2003). Increased stress burden, stress response, pain catastrophising cognitions, poor social functioning and psychiatric comorbidity (anxiety and depression) are contributing factors (Riegel 2014).

• Dyssynergic voiding associated with bladder neck hypertrophy is detected in patients suffering from refractory CP/CPPS (Dellabella 2006; Hruz 2003). Intra‐prostatic urinary reflux and increased intra‐prostatic pressure is associated with inflammation in CP/CPPS (Kirby 1982; Mehik 2002).

• Other theories described for this condition include: adrenal axis abnormalities (Anderson 2008), pelvic floor muscles dysfunction (Hetrick 2006; Shoskes 2008a), pelvic nerves entrapment (Antolak 2002), genetic predisposition to inflammation (Shoskes 2002), and oxidative stress (Arisan 2006).

Description of the intervention

There are a wide variety of interventions for treating CP/CPPS, each one addressing a different pathophysiological or symptomatic framework. The diversity of available interventions reflects the complexity of the condition and how little is known about its determinants.

Management of CP/CPPS involves a multimodal and tailored approach (Rees 2015; Shoskes 2008b). Some of the strategies used alone or in combination are the following.

Pharmacological interventions:

• Alpha blockers

• 5‐alpha reductase inhibitors

• Antibiotic therapy (quinolones, tetracyclines and other agents)

• Analgesics (nonsteroidal anti‐inflammatory drugs (NSAIDs), pregabalin)

• Phytotherapy (pollen extract and bioflavonoids)

• Botulinum toxin A

• Allopurinol

• Traditional medicine (traditional Chinese medicine, etc.)

• Other pharmacological agents

Non‐Pharmacological interventions:

• Acupuncture and electroacupuncture

• Local Thermotherapy

• Extracorporeal shockwave therapy

• Myofascial trigger point release

• Biofeedback

• Psychological support

• Prostatic surgery

• Other miscellaneous non‐pharmacological therapies

Multimodal approaches:

• Combination therapy: alpha blockers plus antibiotics, antibiotics plus analgesics, etc.

• Clinical phenotyping: UPOINT strategy

Adverse effects

Common side effects of pharmacological regimes include (Brunton 2011) the following.

• Alpha blockers: hypotension, ejaculatory dysfunction, headache, dizziness, and nasal congestion

• 5‐alpha‐reductase inhibitors: decreased libido, impotence, potentiation of hypotension (in combination with alpha blockers)

• Quinolones: gastrointestinal discomfort, headache, dizziness, rash, and tendinopathy

• Tetracyclines: gastrointestinal discomfort, rash, teeth discolouration, and hepatotoxicity

• NSAIDs: peripheral edema, rash, dyspepsia, peptic ulcer and bleeding, renal and hepatic injury, and increased risk of adverse cardiovascular events

• Phytotherapy: gastrointestinal discomfort and allergic reactions

The most common side effect in physical therapies is pain worsened during or immediately after the procedure (Fitzgerald 2013).

How the intervention might work

Pharmacological interventions

Alpha blockers reduce the autonomic sympathetic tone in the bladder neck and prostate, improving urinary flow and lower urinary tract symptoms. 5‐alpha‐reductase inhibitors reduce the production of dihydrotestosterone and, consequently, the size of the prostatic gland dependent on the stimulation of this hormone. This might reduce pain and impaired voiding (Brunton 2011).

NSAIDs are antagonists to the cyclooxygenases enzymes (COX) type 1 and 2 and their pro‐inflammatory subproducts (Brunton 2011). Both nonselective and selective (COX‐2) inhibitors could therefore decrease inflammatory mediated pain in CP/CPPS.

Phytotherapy includes the use of pollen extract and bioflavonoids that appear to have anti‐inflammatory properties, decreasing acinar cell proliferation and the production of interleukin‐6, tumor necrosis factor α, and other pro‐inflammatory cytokines (Capodice 2005; Kamijo 2001).

Even if CP/CPPS is defined when no bacterial cause can be identified, antibiotics have been used to treat it under the assumption of the existence of an occult or under‐treated infection (Hou 2012).

Allopurinol would reduce the prostatic secretions of purine and pyrimidine base containing metabolites in urine. These metabolites could be responsible for prostatic inflammation through urinary reflux (McNaughton 2002).

Botulinum toxin A has denervating properties and also causes reduction in pain mediators when applied to the prostate in animal models. It also causes apoptosis and involution of the prostate gland (Chuang 2006).

Nonpharmacological interventions

Acupuncture targets specific cutaneous points representing various internal organs using fine needle insertion and sometimes adding electric current to increase stimulation (electroacupuncture). In animal models electroacupuncture has anti‐inflammatory properties and activates analgesic neurotransmitters (Kim 2006).

Locally induced hyperthermia, using transrectal or transurethral procedures, could decrease oxygen free radicals associated with prostatic inflammation (Gao 2012).

Myofascial trigger points release targets pelvic floor musculature dysfunction as a potential cause or contributor to CP/CPPS (Fitzgerald 2013). Biofeedback also addresses pelvic floor muscle through initial contraction in order to achieve further relaxation (Capodice 2005).

It has been suggested that psychological treatments could be helpful in all types of chronic pain syndromes and the psychiatric comorbidity associated with the condition (e.g. depression secondary to chronic pain) (Riegel 2014).

Clinical phenotyping

Clincal phenotyping is a strategy that was developed in order to deliver customised treatment in an aetiologic framework (Shoskes 2008b). The UPOINT system addresses six domains: Urinary symptoms, Psychosocial dysfunction, Organ specific findings, Infection, Neurologic dysfunction and Tenderness of muscles, and offers an algorithmic approach for the use of the aforementioned interventions. The number of affected domains holds a significant correlation with the prostatitis symptoms score and the addition of a Sexual dysfunction domain (UPOINT(S)) improves accuracy in stratification of symptom severity (Magri 2010).

Why it is important to do this review

The Cochrane Urology Group undertook an extensive prioritisation exercise to identify a core portfolio of the most clinically‐important titles. Consequently, this title was identified as a clinically‐important priority by the urology expert panel for development, maintenance, and investment of resources by the editorial base.

CP/CPPS is a prevalent condition amongst men and it causes significant impairment of quality of life. There was a previous Cochrane Review on the same subject but with a different methodological approach (McNaughton Collins 1999). Other non‐Cochrane systematic reviews were also undertaken in previous years: some of them focused on individual interventions (Qin 2016; Yang 2006; Zhu 2014), while others had a wider scope of interventions (Anothaisintawee 2011; Cohen 2012; Magistro 2016). We consider that a new and updated Cochrane Review is needed in order to critically summarise the body of evidence for this complex condition using the GRADE approach, thus providing key information about the best estimate of the magnitude of the effect in relative terms and absolute differences for patient‐important outcomes. Previous systematic reviews did not use this approach and had variable adherence to the rigorous methodology recommended by Cochrane.

The protocol for this review was first published in August 2016 with the title "Interventions for treating chronic prostatitis/chronic pelvic pain syndrome" (Franco 2016). Due to the retrieval of a significant amount of included studies, the review team and the Cochrane Urology Group decided to split the review in two more narrowly defined reviews: "Non‐pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome" and "Pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome".

Objectives

To assess the effects of pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomised controlled trials (RCTs). We will include studies regardless of their publication status or language of publication.

Types of participants

We will include men of all ages, regardless of social condition or ethnic origin, suffering from chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) according with type III prostatitis of the NIH classification.

If we identify studies in which only a subset of participants are relevant to this review, we will include such studies if data are available separately for the relevant subset.

Types of interventions

We plan to investigate the following comparisons of experimental intervention versus comparator intervention. Concomitant interventions will have to be the same in the experimental and comparator groups to establish fair comparisons. We will perform a condition‐based comprehensive bibliographic search in order to find all interventions tested so far for CP/CPPS; therefore, some of them might not be listed in this section.

Pharmacological interventions:

• Alpha blockers

• 5‐alpha reductase inhibitors

• Antibiotic therapy (quinolones, tetracyclines and other agents)

• Analgesics (nonsteroidal anti‐inflammatory drugs (NSAIDs), pregabalin)

• Phytotherapy (pollen extract and bioflavonoids)

• Botulinum toxin A

• Allopurinol

• Traditional medicine (traditional Chinese medicine, etc.)

• Other pharmacological agents

Multimodal approaches:

• Combination pharmacological therapy: alpha blockers plus antibiotics, antibiotics plus analgesics, etc.

Comparator interventions

• Placebo

• No treatment

• Other types of pharmacological interventions

Comparisons

We will perform head‐to‐head comparisons or intervention versus placebo/no treatment comparisons. Pharmacological treatments will be compared by drug and by class. For example:

• Alpha blockers versus placebo

• Alpha blockers plus quinolones versus placebo

And also

• Tamsulosin versus placebo

• Tamsulosin plus ciprofloxacin versus placebo

Those studies evaluating the comparison between pharmacological and non‐pharmacological interventions and those who combine non‐pharmacological and pharmacological interventions in the same arm will not be included in this review in order to prevent overlapping with the review "Non‐pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome". For the same reason, we will not include studies evaluating clinical phenotyping in this review since this intervention could comprise non‐pharmacological interventions.

Types of outcome measures

We will not use the measurement of the outcomes assessed in this review as an eligibility criterion.

Primary outcomes

• Effectiveness of treatment: chronic prostatitis symptoms measured by the National Institutes of Health Chronic Prostatitis Symptom Index (NIH‐CPSI) as total score and sub‐scores measurements, when possible, and other validated scales

• Adverse events: treatment intolerance, side effects of the interventions

Secondary outcomes

• Sexual dysfunction measured by validated scales (e.g. International Index of Erectile Function)

• Urinary symptoms measured by IPPS (International Prostate Symptom Score) or AUA‐7 (American Urological Association symptom score)

• Quality of life (QoL) and health‐related quality of life (HRQoL): indicated by, for example, the Medical Outcomes Study Short Form 36 (SF‐36), the Social Adjustment Survey (SAS‐WR), the Sickness Impact Profile (SIP), the general health questionnaire (GHQ), and the EuroQOL‐5D (EQ‐5D) or other validated scales

• Psychological outcomes indicated by scores such as depression scores (Hamilton Depression Rating Scale (HAM‐D) score, Hospital Anxiety Depression Scale) or other validated scales

Main outcomes for 'Summary of findings' table

We will present a 'Summary of findings' table reporting the following outcomes listed according to priority.

1. Prostatitis symptoms

2. Adverse events of interventions

3. Sexual dysfunction

4. Quality of life or health‐related quality of life

5. Depression and anxiety

Search methods for identification of studies

We will search for all published and unpublished RCTs meeting our stated inclusion/exclusion criteria, without restrictions on language, publication date or publication status, and in consultation with the Cochrane Urology Group Information Specialist.

Electronic searches

Published, unpublished and ongoing studies will be identified by searching the following databases from their inception:

• PubMed (1946 onwards)

• Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) in the Cochrane Library

• Embase Elsevier (1947 onwards)

• PsycINFO OVID (1887 onwards)

• CINAHL EBSCO (1937 onwards)

• ClinicalTrials.gov (www.clinicaltrials.gov)

• ISRCTN Registry (BioMed Central; http://www.isrctn.com/)

• World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch)

The search strategies for databases will be modelled on the search strategy designed for PubMed (Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6). The PubMed search will utilise the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision; Lefebvre 2011). The Embase search will utilise the trial filter for therapy, maximising sensitivity developed by the Health Information Research Unit (HIRU) at McMaster University, adapted from OVID to the Elsevier interface (HIRU 2015). For CENTRAL and clinical trials registries filters are not applicable. We will not use filters for PsycINFO and CINAHL because the results likely to be obtained are very few.

If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes.

Searching other resources

We will try to identify other potentially‐eligible trials or ancillary publications by searching the reference lists of retrieved included trials and relevant reviews, meta‐analyses and health technology assessment reports. We will also contact authors of included studies to identify any further studies that we may have missed. We will contact drug and device manufacturers for ongoing or unpublished trials. We will search abstract proceedings of the American Urological Association, European Association of Urology and Society of Sexual Medicine of the last three years for unpublished studies.

We will also search other grey literature sources such as:

• Open Grey (http://www.opengrey.eu/)

• New York Academy of Medicine Grey Literature Report (http://www.greylit.org/)

• Google Scholar

Data collection and analysis

Selection of studies

We will use reference management software (EndNote X7) to identify and remove duplicate records. Two review authors (JVAF, VV) will independently scan the abstract, title, or both, of remaining records retrieved, to determine which studies should be assessed further. Two review authors (JVAF, VV) will investigate all potentially‐relevant records as full text, map records to studies, and classify studies as included studies, excluded studies, studies awaiting classification, or ongoing studies in accordance with the criteria for each provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will resolve any discrepancies through consensus or recourse to a third review author (FIT). If resolution of a disagreement is not possible, we will designate the study as 'awaiting classification' and we will contact study authors for clarification. We will document reasons for exclusion of studies that may have reasonably been expected to be included in the review in a 'Characteristics of excluded studies' table. We will present an adapted PRISMA flow diagram showing the process of study selection (Liberati 2009).

Data extraction and management

We will develop a dedicated data abstraction form that we will pilot test ahead of time.

For studies that fulfil inclusion criteria, two review authors (JVAF, VV) will independently abstract the following information, which we will provide in the 'Characteristics of included studies' table:

• Study design

• Study dates (if dates are not available then this will be reported as such)

• Study settings and country

• Participant inclusion and exclusion criteria

• Participant details, baseline demographics

• The number of participants by study and by study arm

• Details of relevant experimental and comparator interventions such as dose, route, frequency, and duration

• Definitions of relevant outcomes, and method and timing of outcome measurement as well as any relevant subgroups

• Study funding sources

• Declarations of interest by primary investigators

We will extract outcomes data relevant to this Cochrane review as needed for calculation of summary statistics and measures of variance. For dichotomous outcomes, we will attempt to obtain numbers of events and totals of population for a 2 x 2 table, as well as summary statistics with corresponding measures of variance. For continuous outcomes we will attempt to obtain means and standard deviations or data necessary to calculate this information. For time‐to‐event outcomes, we will attempt to obtain hazard ratios (HRs) with corresponding measures of variance or data necessary to calculate this information.

We will resolve any disagreements by discussion, or, if required, by consultation with a third review author (FIT).

We will provide information, including trial identifier, about potentially‐relevant ongoing studies in the table 'Characteristics of ongoing studies'.

We will attempt to contact authors of included studies to obtain key missing data as needed.

Dealing with duplicate and companion publications

In the event of duplicate publications, companion documents or multiple reports of a primary study, we will maximise yield of information by mapping all publications to unique studies and collating all available data. We will use the most complete data set aggregated across all known publications. In case of doubt, we will give priority to the publication reporting the longest follow‐up associated with our primary or secondary outcomes.

Assessment of risk of bias in included studies

Two review authors (JVAF, VV) will assess the risk of bias of each included study independently. We will resolve disagreements by consensus, or by consultation with a third review author (FIT).

We will assess risk of bias using Cochrane's 'Risk of bias' assessment tool (Higgins 2011b). We will assess the following domains:

• Random sequence generation (selection bias)

• Allocation concealment (selection bias)

• Blinding of participants and personnel (performance bias)

• Blinding of outcome assessment (detection bias)

• Incomplete outcome data (attrition bias)

• Selective reporting (reporting bias)

• Other sources of bias

We will judge risk of bias domains as 'low risk', 'high risk' or 'unclear risk' and will evaluate individual bias items as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). We will present a 'Risk of bias' summary figure to illustrate these findings.

For performance bias (blinding of participants and personnel) and detection bias (blinding of outcome assessment), we will evaluate the risk of bias separately for each outcome, and we will group outcomes according to whether measured subjectively or objectively when reporting our findings in the 'Risk of bias' tables.

We will also assess attrition bias (incomplete outcome data) on an outcome‐specific basis, and will group outcomes with like judgements when reporting our findings in the 'Risk of bias' tables.

We will further summarise the risk of bias across domains for each outcome in each included study, as well as across studies and domains for each outcome.

All endpoints are subjective outcomes.

Measures of treatment effect

We will express dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs). We will express continuous data as mean differences (MDs) with 95% CIs unless different studies use different measures to assess the same outcome, in which case we will express data as standardised mean differences with 95% CIs. We will express time‐to‐event data as hazard ratios (HRs) with 95% CIs.

For the primary outcome we will define a minimal clinically important change in NIH‐CPSI score as a 25% decrease or a 6‐point reduction from baseline (Nickel 2003b).

Unit of analysis issues

The unit of analysis will be the individual participant. Should we identify cross‐over trials, cluster‐randomised trials, or trials with more than two intervention groups for inclusion in the review, we will handle these in accordance with guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c).

Dealing with missing data

We will obtain missing data from study authors, if feasible, and will perform intention‐to‐treat (ITT) analyses if data are available; otherwise we will perform available case analyses. We will investigate attrition rates, such as dropouts, losses to follow‐up and withdrawals, and will critically appraise issues of missing data. We will not impute missing data.

Assessment of heterogeneity

In the event of excessive heterogeneity unexplained by subgroup analyses, we will not report outcome results as the pooled effect estimate in a meta‐analysis but will provide a narrative description of the results of each study.

We will identify heterogeneity (inconsistency) through visual inspection of the forest plots to assess the amount of overlap of CIs, and the I² statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta‐analysis (Higgins 2002; Higgins 2003). We will interpret the I² statistic as follows.

• 0% to 40%: may not be important

• 30% to 60%: may indicate moderate heterogeneity

• 50% to 90%: may indicate substantial heterogeneity

• 75% to 100%: considerable heterogeneity

When we find heterogeneity, we will attempt to determine possible reasons for it by examining individual study and subgroup characteristics.

Assessment of reporting biases

We will attempt to obtain study protocols to assess for selective outcome reporting.

If we include 10 studies or more investigating a particular outcome, we will use funnel plots to assess small study effects. Several explanations can be offered for the asymmetry of a funnel plot, including true heterogeneity of effect with respect to trial size, poor methodological design (and hence bias of small trials) and publication bias. We will, therefore, interpret results carefully.

Data synthesis

Unless there is good evidence for homogeneous effects across studies, we will summarise data using a random‐effects model. We will interpret random‐effects meta‐analyses with due consideration of the whole distribution of effects. In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). For dichotomous outcomes we will use the Mantel‐Haenszel method; for continuous outcomes we will use the inverse variance method; and for time‐to‐event outcomes we will use the generic inverse variance method. We will use RevMan 2014 software to perform analyses.

Subgroup analysis and investigation of heterogeneity

We expect the following characteristics to introduce clinical heterogeneity, and plan to carry out subgroup analyses with investigation of interactions.

• Patients' characteristics: symptom severity at recruitment, age, presence of clinical comorbidities (irritable bowel syndrome, fibromyalgia, interstitial cystitis)

• Duration of the intervention in weeks (for example, less than 12 weeks or more than 12 weeks)

We will use the test for subgroup differences in RevMan 2014 to compare subgroup analyses if there are sufficient studies.

Sensitivity analysis

We plan to perform sensitivity analyses in order to explore the influence of the following factors (when applicable) on effect sizes.

• Restricting the analysis by taking into account risk of bias, by excluding studies at 'high risk' or 'unclear risk'

• Explore the impact of re‐expressing symptom severity as a dichotomous outcome

'Summary of findings' table

We will present the overall quality of the evidence for each outcome according to the GRADE approach, which takes into account five criteria not only related to internal validity (risk of bias, inconsistency, imprecision, publication bias), but also to external validity, such as directness of results (Guyatt 2008). For each comparison, two review authors (JVAF, VV) will independently rate the quality of evidence for each outcome as 'high', 'moderate', 'low', or 'very low' using GRADEpro GDT. We will resolve any discrepancies by consensus, or, if needed, by arbitration by a third review author (FIT). For each comparison, we will present a summary of the evidence for the main outcomes in a 'Summary of findings' table, which provides key information about: the best estimate of the magnitude of the effect in relative terms and absolute differences for each relevant comparison of alternative management strategies; numbers of participants and studies addressing each important outcome; and the rating of the overall confidence in effect estimates for each outcome (Guyatt 2011; Schünemann 2011). If meta‐analysis is not possible, we will present results in a narrative 'Summary of findings' table.

Appendices

Appendix 1. PubMed search strategy

#1 "Prostatitis"[Mesh]

#2 prostatit*[tiab]

#3 prostatodyn*[tiab]

#4 #1 OR #2 OR #3

#5 “Pelvic Pain"[Mesh]

#6 pelvic pain[tiab]

#7 CPP*[tiab]

#8 #5 OR #6 OR #7

#9 #4 AND #8

#10 "Asymptomatic Diseases"[Mesh]

#11 asymptom*[tiab]

#12 nonsymptom*[tiab]

#13 non symptom*[tiab]

#14 abacterial*[tiab]

#15 nonbacterial*[tiab]

#16 non bacterial*[tiab]

#17 aseptic*[tiab]

#18 nonseptic*[tiab]

#19 non septic*[tiab]

#20 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

#21 #4 AND #20

#22 chronic prostatitis chronic pelvic pain syndrome[tiab] OR CP CPP*[tiab]

#23 #9 OR #21 OR #22

#24 "Randomized Controlled Trial"[Publication Type]

#25 "Controlled Clinical Trial"[Publication Type]

#26 randomized[tiab]

#27 placebo[tiab]

#28 "drug therapy"[Subheading]

#29 randomly[tiab]

#30 trial[tiab]

#31 groups[tiab]

#32 #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31

#33 "Animals"[Mesh] NOT "Humans"[Mesh]

#34 #32 NOT #33

#35 #23 AND #34

Appendix 2. CENTRAL search strategy

#1 [mh prostatitis]

#2 prostatit*:ti,ab

#3 prostatodyn*:ti,ab

#4 #1 or #2 or #3

#5 [mh "pelvic pain"]

#6 pelvic near/3 pain:ti,ab

#7 CPP*:ti,ab

#8 #5 or #6 or #7

#9 #4 and #8

#10 [mh "asymptomatic diseases"]

#11 asymptom*:ti,ab

#12 nonsymptom*:ti,ab

#13 non near/3 symptom*:ti,ab

#14 abacterial*:ti,ab

#15 nonbacterial*:ti,ab

#16 non near/3 bacterial*:ti,ab

#17 aseptic*:ti,ab

#18 nonseptic*:ti,ab

#19 non near/3 septic*:ti,ab

#20 #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19

#21 #4 and #20

#22 prostatit* and (pelvic near/3 pain or CP CPP*)

#23 #9 or #21 or #22

Appendix 3. Embase search strategy

#1 “prostatitis”/exp

#2 prostatit*:ab,ti

#3 prostatodyn*:ab,ti

#4 #1 OR #2 OR #3

#5 “pelvic pain”/exp

#6 cpp*:ab,ti

#7 (pelvi* NEAR/3 pain):ab,ti

#8 #5 OR #6 OR #7

#9 #4 AND #8

#10 “asymptomatic disease”/exp

#11 asymptom*:ab,ti

#12 nonsymptom*:ab,ti

#13 (non NEAR/3 symptom*):ab,ti

#14 abacterial*:ab,ti

#15 nonbacterial*:ab,ti

#16 (non NEAR/3 bacterial*):ab,ti

#17 aseptic*:ab,ti

#18 nonseptic*:ab,ti

#19 (non NEAR/3 septic*):ab,ti

#20 #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18

OR #19

#21 #4 AND #20

#22 chronic:ab,ti AND (prostatitis NEAR/3 pelvi* NEAR/3 pain):ab,ti

#23 #9 OR #21 OR #22

#24 random*:ab,ti

#25 “clinical trial*”

#26 “health care quality”/exp

#27 #24 OR #25 OR #26

#28 #23 AND #27

Appendix 4. PsycINFO search strategy

1 prostatitis.mp.

2 prostatit*.ab,ti.

3 prostatodyn*.ab,ti

4 1 or 2 or 3

5 pelvic pain.mp.

6 (pelvi* adj3 pain).mp.

7 cpp*.ab,ti.

8 5 or 6 or 7

9 4 and 8

10 asymptom*.ab,ti.

11 nonsymptom*.ab,ti.

12 (non adj3 symptom*).ab,ti.

13 abacterial*.ab,ti.

14 nonbacterial*.ab,ti.

15 (non adj3 bacterial*).ab,ti.

16 aseptic*.ab,ti.

17 nonseptic*.ab,ti.

18 (non adj3 septic*).ab,ti.

19 10 or 12 or 13 or 14 or 15 or 16 or 17 or 18

20 4 and 19

21 (chronic prostatitis adj3 pelvi* adj3 pain).ab,ti.

22 9 or 20 or 21

Appendix 5. CINAHL search strategy

S1 MH “Prostatitis”

S2 TI prostatit* OR AB prostatit*

S3 TI prostatodyn* OR AB prostatodyn*

S4 S1 OR S2 OR S3

S5 MH “Pelvic Pain”

S6 TI pelvic pain OR AB pelvic pain

S7 TI cpp* OR AB cpp*

S8 S5 OR S6 OR S7

S9 S4 AND S8

S10 TI asymptom* OR AB asymptom*

S11 TI nonsymptom* OR AB nonsymptom*

S12 TI non N3 symptom* OR AB non N3 symptom*

S13 TI abacterial* OR AB abacterial*

S14 TI nonbacterial* OR AB nonbacterial*

S15 TI non N3 bacterial* OR AB non N3 bacterial*

S16 TI aseptic* OR AB aseptic*

S17 TI nonseptic* OR AB nonseptic*

S18 TI non N3 septic* OR AB non N3 septic*

S19 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR

S18

S20 S4 AND S19

S21 TI chronic prostatitis/chronic pelvic pain syndrome OR chronic prostatitis

OR AB chronic prostatitis/chronic pelvic pain syndrome OR TI chronic

prostatitis chronic pelvic pain syndrome OR chronic prostatitis OR AB

chronic prostatitis chronic pelvic pain syndrome

S22 S9 OR S20 OR S21

Appendix 6. ClinicalTrials.gov/Controlled Trials/WHO ICTRP search strategy

Prostatitis AND (Pelvic Pain OR CPP OR CP CPPS)

Contributions of authors

Juan VA Franco (JVAF): wrote the protocol.

Tarek Turk (TT): contributed to the methods section of the protocol.

Federico Ignacio Tirapegui (FIT): contributed to the background section of the protocol.

Virginia Garrote (VG): designed the search strategies and wrote the Search methods for identification of studies section.

Valeria Vietto (VV): wrote the protocol.

Sources of support

Internal sources

• Instituto Universitario Hospital Italiano (IUHI), Argentina.

  VV is the Cochrane Center Coordinator and VG is the Head Librarian; they both receive a salary from the IUHI. JVAF works as a fellow researcher in systematic reviews for the IUHI.

External sources

• No sources of support supplied

Declarations of interest

JVAF: none known.

TT: none known.

FIT: none known.

VG: none known.

VV: none known.

Notes

We have based parts of the Methods section and Appendix 1 of this protocol on a standard template developed by the Cochrane Metabolic and Endocrine Disorders Group, which has been modified and adapted for use by the Cochrane Urology Group.

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