Introduction

Prostatitis, by its very name, conjures up the idea of an inflamed (. . . itis) prostate (prostat . . .). For clinicians, inflammation in the urinary tract is invariably associated with infection. Therefore, it is no surprise that therapy for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) has traditionally been directed towards a prostate-centric infectious and/or inflammatory condition of the male lower urinary tract [1]. This chapter will review the evidence available for the use of antimicrobials, anti-inflammatories and the two major classes of agents employed in treating benign prostate disease (alpha-blockers and 5-alpha-reductase inhibitors).

A quick review of the prostatitis syndromes is necessary in order to understand therapeutic approaches to CP/CPPS [2–4]. Category I acute bacterial prostatitis is an acute bacterial infection of the prostate gland associated with local pain, obstructive voiding symptoms, fever and other systemic manifestations of a serious infection. Treatment is antibiotics. Category II chronic bacterial prostatitis is a chronic infection of the prostate associated with recurrent urinary tract infections. Patients are often asymptomatic between infections. Treatment consists of long-term antibiotics, usually trimethoprim-sulfamethoxazole or preferably a fluoroquinolone (ciprofloxacin or levofloxacin). Category III CP/CPPS is characterized by chronic pelvic (and/or genitourinary) pain/discomfort that is not associated with recurrent or active infection. This chapter will discuss the treatment of this category.

Chronic prostatitis/chronic pelvic pain syndrome is a major clinical problem. The prevalence rate of physician-diagnosed prostatitis in Olmsted County was 9% [5]; population-based surveys have estimated that between 6% and 12% of men experience prostatitis-like symptoms [6,7]. The quality of life is dismal [8] and the costs to society enormous[9]. The etiology of prostatitis in the majority of men whose symptoms persist longer than 3 months is believed to be noninfectious [3,4].

The literature is replete with many small, under-powered, poorly designed trials in CP/CPPS. This has changed with the general acceptance of the NIH classification system and clinical definition of CP/CPPS [2], the development and validation of the NIH Chronic Prostatitis Symptom Index (CPSI) as an outcome tool [10,11] and description of a properly designed clinical trial in CP/CPPS [12,13]. Nickel described the four requirements that would constitute clinical trial data that could be used to draw evidence-based treatment recommendations in CP/CPPS [1]:

• NIH classification system for definition and characterization of patients
  
• randomized placebo-controlled design
  
• validated outcome parameters (such as the NIH-CPSI)
  
• peer reviewed (published in peer-reviewed literature).

Papers published or accepted for publication in the peer-reviewed journals were included in this review. Papers published in nonpeer-reviewed supplements were not included. The manuscript list was obtained through the major databases covering the last 10 years (e.g. Medline, EMBASE, Cochrane Library, Biosis, Science Citation Index). The tables of contents of the major journals of urology and other relevant journals for the previous 3 months were reviewed to take into account possible delay in indexation of papers in the databases. These approaches identified multiple references. After reviewing the titles and abstracts, articles (for the most part that met the criteria noted above) were identified for detailed review.

Literature search

Search terms employed included “prostatitis,” “pelvic pain,” “chronic pelvic pain syndrome,” “clinical trials,” “antibiotics,” “antimicrobials.”

Evidence

Prospective nonrandomized or uncontrolled trials [14,15] have led to recommendations that antibiotics should be employed in the treatment of CP/CPPS, particularly the inflammatory subtype (Category IIIA) [16]. Two multicenter, randomized, placebo-controlled studies have assessed the efficacy of 6 weeks of levofloxacin [17] and ciprofloxacin [18] in men with CP/CPPS. In these trials the participants had chronic symptoms for a long duration (many years) and had been heavily treated (including treatment with antibiotics). In the study by Nickel and associates [17], 80 patients were randomized to levofloxacin or placebo while in the NIH-sponsored study reported by Alexander and colleagues [18], 196 men with CP/CPPS were randomized in a two-by-two factorial design to ciprofloxacin, tamsulosin, the combination of ciprofloxacin and tamsulosin or placebo. In both of these prospective controlled multicenter trials, no significant difference was reported between fluoroquinolone and placebo in terms of symptom amelioration.

Comment

Critical evaluation of the two randomized, placebo-controlled trials evaluating antimicrobials convincingly demonstrates the futility of employing antibiotics in CP/CPPS men suffering for a long duration (many years in these studies) who had been heavily pretreated (received antibiotics in the past for prostatitis) (Grade 1A). However, nonplacebo-controlled trials suggest that men with early diagnosis (4–8 weeks) who had not been previously treated with antibiotics may respond to a trial course of antimicrobial therapy [14,19] (Grade 2B).

Literature search

Search terms employed included “prostatitis,” “pelvic pain,” “chronic pelvic pain syndrome,” “clinical trials,” “anti-inflammatories,” “nonsteroidal,” “COX-2 inhibitors.”

Evidence

The results of a North American randomized placebo-controlled trial comparing the cyclo-oxygenase-2 (COX-2) inhibitor rofecoxib to placebo [20] indicated that some men with CPPS benefited (in terms of pain and quality of life) from rofecoxib therapy compared with placebo. In this study, in which 161 patients were randomized to rofecoxib 25 mg, rofecoxib 50 mg or placebo, only patients on the high dose showed statistically clinical improvement compared to the placebo. Very few patients, however, had complete resolution of their symptoms [20].

The clinical and pathological characteristics of CP/CPPS are similar to those of interstitial cystitis and a number of small studies examining the efficacy of pentosan polysulfate, a glycosaminoglycan that has some anti-inflammatory activity used in the treatment of interstitial cystitis, suggested benefit [21]. The results of a multicenter, randomized, placebo-controlled trial that randomized 100 men to pentosan polysulfate 900 mg/day (three times the usual dose) or placebo indicated that this medication provided modest benefit for some men with CPPS [22]. Quercetin, a natural bioflavanoid with potent anti-inflammatory characteristics (for a phytotherapuetic agent), has been shown to provide a statistically and clinically significant benefit compared to placebo in a very small, single-center pilot study [23]. A very small (17 patients in total) single-center study [24] showed no obvious benefits of zafirlukast, a leukotriene antagonist, compared to placebo on the symptoms of Category IIIA CP/CPPS.

Comment

Critical evaluation of these trials would suggest that high dose anti-inflammatory therapy continued for a prolonged duration may have a modest ameliorative effect in some patients (Grade 1B). The results from the small but placebo-controlled trial with quercetin are intriguing and should be further investigated. Pentosan polysulfate might be more effective in men whose CPPS is related to a primary bladder etiology (interstitial cystitis). Anti-inflammatory therapy cannot be recommended as a monotherapy for CP/CPPS, but could be considered in a multimodal therapeutic regime.

Literature search

Search terms employed included “prostatitis,” “pelvic pain,” “chronic pelvic pain syndrome,” “clinical trials,” “alpha-blockers,” “alpha-receptor antagonists,” “terazosin,” “alfuzosin,” “doxazosin,” “tamsulosin,” “5-alpha-reductase” “inhibitors,” “finasteride.”

Evidence

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