Pharmacotherapy strategies in chronic prostatitis/chronic pelvic pain syndrome management

Abstract

Importance of the field: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the most common diagnoses arising out of urologic office visits. It is a costly problem and sufferers compare the effect of this syndrome on quality of life as being similar to the effects of diabetes mellitus and myocardial infarction. The syndrome is variable in presentation and symptom management and efficacy will vary between inflicted men.

Areas covered in this review: CP/CPPS is not highly responsive to therapy. As such, it is often a waxing and waning illness with symptoms in multiple domains, including urinary symptoms, pain and ejaculatory dysfunction. The pharmacotherapeutic options and management strategies for CP/CPPS presented in this review are based on the published literature from September 1989 to January 2010. When available, randomized, placebo-controlled studies were reviewed to aid in making definitive recommendations for treatment strategies.

What the reader will gain: The reader will be familiarized with the commonly used classes of pharmaceutical and non-pharmaceutical therapies. Readers will then use the efficacy data to inform treatment decisions for patients with disparate symptomatology. This will be crystallized in the author's treatment algorithm and summary statement.

Take home message: Many practitioners use antimicrobials as a first-line agent, particularly a fluoroquinolone, such as levofloxacin. Trimethoprim/sulfamethoxazole is another medication alternative, with comparable response rates. Many afflicted men will have significant improvement on a 4- to 6-week regimen of a fluoroquinolone antibiotic. Second-line pharmacotherapy includes alpha-blockers, 5-alpha reductase inhibitors and anti-inflammatories for men with urinary symptoms or pain as a predominant symptom domain. Other pharmacotherapy includes steroids, glycosaminoglycans and phytotherapy. Surgical options are generally not recommended for CP/CPPS. Despite the lack of curative therapies, effective symptom management can be achieved with knowledge of the classes of pharmacotherapy. Therapeutic decisions can be based on the symptoms of the patient. Pelvic floor physical therapy is a useful second-line therapy in the author's opinion, but randomized controlled trials and standardization of technique for CP/CPPS are needed before recommendations can be substantiated.

Keywords::

• chronic pelvic pain syndrome
• NIH-CPSI
• prostatitis

1. Introduction

Prostatitis is a commonly diagnosed ailment that results in 2 million physician visits annually. Using non-Medicare rates for outpatient visits and tests/procedures, the annual per person cost is about $6500, creating a multibillion dollar expenditure [1]. Prostatitis also has a profound effect on the quality of life of afflicted men similar to the impact of unstable angina and a myocardial infarction. ‘Prostatitis’ is actually a term applied to four separate entities. The National Institutes for Health (NIH) devised a classification including: acute bacterial prostatitis (ABP), chronic bacterial prostatitis (CBP), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and asymptomatic inflammatory prostatitis (AIP) (Table 1) [2]. AIP is generally not symptomatic and is diagnosed histologically during the evaluation of prostate cancer or infertility. In most cases, AIP does not warrant specific therapy. CP/CPPS is not characterized by bacterial infection and is by far the most prevalent subtype of the prostatitis syndrome, representing 95% of all cases [3]. Antibiotics have been considered first-line pharmacotherapy in ABP, CBP and CP/CPPS, although they are more efficacious in the bacterial entities, ABP and CBP. Antibiotics have less than optimal results in CP/CPPS, resulting in significant long-term improvement in only 50 – 65% of men [4,5]. Moreover, most pharmacotherapies employed for CP/CPPS fail to ameliorate symptoms adequately [6]. As such, multiple medications have been tried.

Table 1. The NIH consensus classification of prostatitis syndromes includes four categories [1].

NIH classification	Definition
Category I – acute bacterial prostatitis	Acute infection of the prostate gland
Category II – chronic bacterial prostatitis	Recurrent infection of the prostate
Category IIIA – inflammatory CPPS	White cells in semen/EPS/VB3 (VB3 or post-prostatic massage)
Category IIIB – non-inflammatory CPPS	No white cells in semen/EPS/VB3
Category IV – asymptomatic inflammatory prostatitis	Abnormal semen analysis Elevated PSA values Incidental findings in biopsied prostate

CPPS: Chronic pelvic pain syndrome; EPS: Expressed prostatic secretions; PSA: Prostate-specific antigen; VB3: Voided bladder urine culture 3.

This review article summarizes the available literature on the various classes of pharmacotherapy and other interventions used in the treatment of CP/CPPS and provide our preferred management strategies for CP/CPPS. This article focuses on category III chronic prostatitis. CP/CPPS can be categorized as inflammatory (IIIA) or non-inflammatory (IIIB), depending on the presence or absence of leukocytes (white blood cells) in the collected expressed prostatic secretions (EPS) and the subsequent urine sample collected (VB3). The presence of leukocytes in the ejaculate are also included in the definition of inflammatory chronic prostatitis or CPPS (IIIA). Type IIIA corresponds to the traditional classification of chronic nonbacterial prostatitis and type IIIB is comparable to prostatodynia [7].

2. Pathophysiology of CP/CPPS

The etiology of CP/CPPS is unknown. Several postulates have been made including infectious, autoimmune, neurologic, detrusor-sphincter dysfunction and psychiatric diseases [8]. By definition, CP/CPPS is not infectious. However, Schaeffer et al. and Zhu et al. have found bacterial DNA in the prostate glands of men with CP/CPPS, despite repeated negative culture results using polymerase chain reaction (PCR) [9,10]. Additionally, Zhu et al. reported symptomatic improvement with oral antibiotics in men with CP/CPPS correlated with the detection of bacterial DNA via PCR in their prostates [10]. This suggests the presence of bacteria, which are difficult to grow in standard culture media, as the causative or initiating agent, similar to the role played by Helicobacter pylori in peptic ulcer disease. A recent study provides further evidence for the role of difficult-to-culture bacteria in men with CP/CPPS. The study evaluated the localization culture results of 194 men over age 18 with CP/CPPS, administered the NIH CPSI questionnaire, and obtained urethral swab specimens and selective samples of urine and expressed prostatic secretion via the Meares–Stamey localization technique. Thirty-eight percent of the men had localization cultures growing Chlamydia trachomatis or Trichomonas vaginalis and 87% of the men had an infectious etiology identified [11]. A popular theory holds that CP/CPPS is not an organ-specific syndrome but a urogenital manifestation of regional or systemic maladies [12,13]. CP/CPPS may be initiated by an inciting agent (e.g., infection, trauma, dysfunctional voiding, autoimmune reaction, chemical irritant) causing inflammation or neurologic damage in and around the prostate (pelvic floor, bladder, perineum, etc.). If not dealt with quickly, peripheral and then central sensitization occurs [14]. The patients can develop pelvic floor neuromuscular dysfunction. The neuromuscular dysfunction can be targeted with pelvic floor physiotherapy [7,15]. The central nervous system sensitization can lead to a chronic neuropathic state and higher brain centers modulate pain and can lead to depression and anxiety, which can be ameliorated with anti-inflammatories, antidepressants and cognitive behavioral therapies [16]. Autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have been associated with men who develop CP/CPPS. Urodynamics often reveal evidence of detrusor sphincter dyssynergia, which provides some evidence of a functional derangement contributing to the symptomatology.

3. Diagnosis

There is no gold standard for diagnostic testing CP/CPPS [17]. The Meares–Stamey four-glass or two-glass tests are localization cultures used to differentiate CP/CPPS from chronic bacterial prostatitis. The Meares-Stamey 4-glass test or 2-glass tests are localization cultures used to differentiate CP/CPPS from chronic bacterial prostatitis. The Meares Stamey test is a sequential collection of urine and expressed prostatic secretions (EPS) before, during, and after a clinician performs a prostate massage. The first 10 mL of voided urine (voided bladder specimen 1 or VB1) represents the urethral flora. After 200mL of urine is voided, the midstream urine culture is collected (VB2), representing the bladder flora. After collecting VB2, the clinician performs the prostatic massage. The EPS and the first voided 10mL after massage (VB3) are then collected and sent for culture and microscopic analysis. A positive finding for bacterial prostatitis includes a cultured colony count of a uropathogen in the EPS or VB3 specimen greater than the VB1 and VB2 specimens by a factor of 10 or more. When non-traditional uropathogens (e.g., Staphylococcus epidermidis or Streptococcus species) are cultured, men are often categorized as having CP/CPPS instead of chronic bacterial prostatitis. However, a study found that both men with traditional uropathogens (e.g., Escherichia coli and Enterococcus faecalis) on localization cultures and men with non-traditional pathogens had similar rates of symptomatic improvement correlated with bacterial eradication on subsequent localization cultures when treated with 4-week courses of fluoroquinolones [18]. This suggests that non-traditional uropathogens may play a role in CBP and may provide a rationale for the efficacy of antibiotic therapy in CP/CPPS.

This localization culture technique can also provide information on inflammation of the prostate (5 – 10 leukocytes per high-power field) to categorize type IIIA and IIIB (< 5 leukocytes per high-power field) [19], but this subtyping does not alter management. The Meares–Stamey test or two-glass tests can differentiate Category II, Category IIIA, or Category IIIB with an accuracy exceeding 90% simply on the basis of urinary white blood cell count and culture results [20].

Chronic bacterial prostatitis is characterized by a history of symptomatic recurrent urinary tract infections documented by cultures with uropathogenic bacteria. If there was no documentation of positive urine cultures during symptomatic periods, microscopic analysis of the urine and urine culture should be obtained when the symptoms recur. The absence of positive urine culture with chronic pelvic pain, with or without obstructive or irritative voiding symptoms, supports the diagnosis of CP/CPPS. Confounding the diagnosis is the fact that up to 8% of men with presumed CP/CPPS and no history of positive urinary tract infections have positive prostate localization cultures. However, a similar number of asymptomatic men will have positive localization cultures as well [21].

Physical examination is non-specific for the diagnosis of CP/CPPS. However, abdominal examination can effectively rule out bladder distention from obstruction and digital rectal exam can be performed as a screen for prostate cancer. A complete blood count and serum prostate-specific antigen (PSA) are not clinically useful measures for CP/CPPS. PSA can, however, be elevated in acute urinary tract infection. It should be followed for normalization after the infection is adequately treated and warrants further evaluation if it remains elevated [22].

Imaging studies are usually low yield, but in men with painful ejaculation a transrectal ultrasound may reveal an enlarged seminal vesicle suggesting an obstructed ejaculatory duct. Nadler and Rubenstein found that surgical removal of the enlarged, partially obstructed seminal vesicle alleviated the patient's pain [23].

The NIH-CPSI score is a 13-item questionnaire used as a research and clinical tool to measure symptom severity and track therapeutic response in men with CP/CPPS. It measures the three most important domains in the chronic prostatitis patient's experience: pain (which includes location, frequency, and severity), voiding symptoms (irritative and obstructive) and impact/quality of life (the impact of the symptoms on the patient's quality of life). It is not a diagnostic tool but should be used prior to initiating therapy to track patients' symptoms and their response to various treatments [6]. A clinically significant reduction in score on the NIH-CPSI index is considered > 6, according to receiver operator curves, although patients can perceive clinical differences at 4 – 6 points [24-27].

4. Treatment

4.1 Antimicrobials

In 2009, Zhu et al. [10] published a report on 94 Chinese men with CP/CPPS and gave them a course of a fluoroquinolone (gatifloxacin 400 mg daily for 4 weeks) with NIH-CPSI questionnaires administered before and 1 month after therapy. The researchers also biopsied the patients' prostates and performed PCR searching for bacterial 16S rRNA. The studies showed 65% of the CP/CPPS patients had bacterial 16S rRNA coding sequences in their prostate and that symptomatic improvement on gatifloxacin was statistically associated with the presence of bacterial 16S rRNA. This suggests that some men have bacterium and presumably bacterial infections as an inciting agent for their CP/CPPS. Fluoroquinolones have been shown to alleviate symptoms in men with Category II, and both inflammatory and non-inflammatory CP/CPPS at nearly equivalent rates [28]. This lends support for the notion that bacteria that are difficult to grow in standard culture media are part of the pathogenesis of CP/CPPS. It also supports a role for the use of antibiotics in the treatment of what is considered a non-infectious entity.

4.2 Alpha-adrenergic blockers

CP/CPPS often presents with voiding symptoms, such as urgency, frequency and incomplete voiding sensation, which can mimic benign prostatic hyperplasia (BPH), in which alpha-blockers are the drug of choice. Small, randomized, placebo-controlled trials evaluating the alpha-blockers tamsulosin, terazosin and alfuzosin showed statistically significant treatment effects [29-31]. However, a well-powered, NIH Chronic Prostatitis Collaborative Research Network (CPCRN) trial of 6 weeks of tamsulosin appears to provide no additional benefit to placebo when used in CP/CPPS patients who were likely treatment refractory patients, including previous treatment with alpha-blockers [31]. Several field experts postulated that longer courses (12 – 14 weeks) of alpha-blockers could provide modest benefits when prescribed to alpha-blocker-naive CP/CPPS men with shorter duration of disease [32]. This hypothesis on duration of therapy in less therapy-refractory patients was published in the New England Journal of Medicine by Nickel et al. in 2008 [33]. The study is a randomized, placebo-controlled trial comparing the effects of 12 weeks alfuzosin and placebo in recently diagnosed (< 2 years and recently symptomatic), alpha-blocker-naive CP/CPPS patients. This study failed to show any benefit of alpha-blockers over placebo in overall NIH-CPSI score or clinical global improvement scores. The combination of an alpha-adrenergic blocker and antibiotic therapy was shown to be more efficacious than antibioitic therapy alone [34]. It seems reasonable to use alpha-blockers in men with lower urinary tract symptoms as a predominant symptom complaint, especially in combination with antimicrobials.

4.3 Anti-inflammatory agents

Anti-inflammatory drugs are therapeutic mainstays in chronic pain syndromes with modest benefit. Nickel et al. randomized 161 patients to 6 weeks of 25 or 50 mg of rofecoxib (Vioxx™), a cyclooxygenase (COX)-2 selective inhibitor or placebo. Only high-dose rofecoxib provided statistically, but only modest clinically, significant benefit compared with placebo treatment [35]. Subsequently, Vioxx was removed from the market in 2004. A small, randomized, single-center, placebo-controlled study with 17 patients evaluated the leukotriene inhibitor, zafirlukast, along with doxycycline for 4 weeks. No significant benefit was demonstrated in this trial [36].

4.4 5-Alpha-reductase inhibitors

Finasteride is widely used pharmacotherapy for BPH. It inhibits the conversion of testosterone to the more potent dihydrotesterone, which inhibits the growth of prostate glands. Finasteride has been shown in small, poorly controlled trials to have a possible effect in CP/CPPS. In 2003, Nickel et al. performed a small, randomized, placebo-controlled study. After 6 months of finasteride compared with placebo, 33% versus 16% had a > 25% decrease in NIH-CPSI score, but the actual magnitude of improvement did not reach statistical significance. The authors do not suggest finasteride as monotherapy in CP/CPPS, unless the patient had concomitant BPH [37]. Finasteride may not be efficacious for up to 1 year in men treated for BPH due to its mechanism of action. Longer studies in men with CP/CPPS could demonstrate the utility of finasteride.

4.5 Glycosaminoglycans

Pentosan polysulfate is a semi-synthetic mucopolysaccharide that is structurally similar to the bladder glycosaminoglycans that form a protective epithelial barrier, although its efficacy in CP/CPPS is thought to be due to its anti-inflammatory effects. It is FDA approved for interstitial cystitis but not for CP/CPPS [38]. Nickel et al. randomized 100 men with CP/CPPS to receive pentosan 300 mg orally three times daily or placebo for 16 weeks. Pentosan improved NIH-CPSI scores, but failed to show a statistically significant (p = 0.068) improvement over placebo (-5.9 with pentosan vs -3.2 with placebo). Patients in the pentosan group also showed non-significant improvement in clinical global improvement scores and quality of life (QOL) scores versus the placebo group [39]. Pentosan should be further evaluated with a randomized, placebo-controlled trial.

4.6 Phytotherapy

Phytotherapy is used for many medical conditions in Europe and Asia but has not been FDA approved for CP/CPPS [8]. Phytotherapy agents thought to be active in CP/CPPS include cernilton, quercetin and saw palmetto.

Cernilton is a bee pollen extract thought to have anti-inflammatory and anti-androgenic activity. German researchers recently evaluated cernilton in a Phase III, randomized, placebo-controlled trial of 12 weeks of placebo versus cernilton extract that contains 63 mg of the defined pollen extract fractions Cernitin T60 (water-soluble fraction) and Cernitin GBX (fat-soluble fraction). The individual domains of pain (p = 0.0086) and quality of life (p = 0.0250), as well as the total NIH-CPSI score (p = 0.0126), were significantly improved after 12 weeks of treatment with pollen extract compared to placebo. Response, defined as a decrease of the NIH-CPSI total score by at least 25% or at least 6 points, was seen in the pollen extract versus placebo group in 70.6 and 50.0% (p = 0.0141), respectively. The mean decrease in total NIH-CPSI score was 7.7 [40].

Quercetin, a polyphenolic bioflavonoid commonly found in red wine, green tea, and onions, may have antioxidant and anti-inflammatory properties. A double-blind, placebo-controlled trial in 30 men evaluated quercetin 500 mg twice daily versus placebo for 4 weeks. The authors concluded that quercetin was associated with a significant improvement in the NIH-CPSI score compared to baseline (p = 0.003) and warrants further study [41].

Quercetin has been shown to augment the effect of a new fluoroquinolone in treatment efficacy in patients with CBP. It may hold further promise as an adjunctive agent for fluoroquinolone therapy for CP/CPPS [42].

Saw palmetto extract is an over-the-counter therapy used by patients with BPH. In 2004, a randomized controlled trial was performed with 64 men with CP/CPPS comparing finasteride and saw palmetto for 1 year. The NIH Chronic Prostatitis Symptom Index score decreased from 23.9 to 18.1 in the finasteride group and changed from 24.7 to 24.6 in the saw palmetto group. CP/CPPS treated with saw palmetto had no appreciable long-term improvement. However, finasteride did show a moderate, durable improvement, but is not recommended for men with CP/CPPS unless they have concurrent symptomatic benign prostatic hyperplasia [37,43].

4.7 Steroids

In recent case reports, seven men with CP/CPPS later developed autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Subsequent steroid therapy improved six of the men's symptoms from the CP/CPPS as well, suggesting that CP/CPPS could be autoimmune in nature. The reports are intriguing and steroids warrant further evaluation in a randomized, placebo controlled trial.

4.8 Posterior tibial nerve stimulation

Authors from Turkey recently evaluated pain scores and NIH-CPSI score improvement in 89 men with CP/CPPS with 12 weeks of posterior tibial nerve stimulation versus sham treatments. Objective success was defined as at least a 50% decrease in the mean scores. A decrease in scores between 25 and 50% was considered a partial response. An objective response was observed with the pain and NIH-CPSI symptom scores after 12 weeks of posterior tibial nerve stimulation (PTNS) in 18 (40%) and 30 (66.6%) of the patients, whereas a partial response was observed in 27 (60%) and 15 (33.3%) of the patients, respectively. Mean symptom scores changed from 23.6 ± 6.3 at baseline to 10.2 ± 3.6. NIH-CPSI symptom scores and pain scores were not changed with sham treatment. The PTNS relieved pain in men with CP/CPPS and decreased NIH-CPSI scores more than most treatments available [44].

4.9 Pelvic floor biofeedback

A recent publication by Nickel et al. describes myofascial pain as one prevalent domain of the CP syndrome. Several authors posit that increased pelvic floor myofascial tone and sensitivity leads to pelvic pain and, in some cases, to dysfunctional urinary voiding. Alpha-blockers are aimed at the smooth-muscle sphincters of the urinary tract, which have been shown recently to be of little efficacy in CP/CPPS. The hypothesis of the mechanism of action of the biofeedback mechanism in treating CP/CPPS is based on the principle that maximum muscle contraction prompts maximum muscle relaxation. This mechanism addresses the chronic pain aspect of CP/CPPS and focuses on muscular re-education, which may ultimately provide symptom relief [45-47]. A new report from China [46] shows amelioration of urinary symptoms and an 8-point improvement on the NIH-CPSI scale with pelvic floor biofeedback (p < 0.05). Studies that reported less symptom improvement with pelvic floor biofeedback did not have standardized approaches. A report by Anderson et al. [47] better delineates the relationships between myofascial trigger points and reported painful sites in men with CP/CPPS. Identifying the site of clusters of trigger points inside and outside the pelvic floor may assist in understanding the role of muscles in this disorder and provide the basis for good randomized controlled trials.

5. Expert opinion

In conclusion, CP/CPPS is a syndrome that needs to be managed as a chronic disease. Shoskes et al. suggests treating this multi-faceted syndrome by directing therapy within the following symptom domains: urinary, psychosocial, organ-specific, infection, neurologic/systemic and tenderness [48]. In this holistic approach, the urologist will need to coordinate the care. In the authors' experience, most pharmacotherapies, aside from fluoroquinolones, lack efficacy early in the course of the disease. Few therapies have data to support their routine usage in the management of CP/CPPS. However, we routinely use a 4- to 6-week course of a fluoroquinolone such as ciprofloxacin or levofloxacin. This antibiotic course can be repeated once if symptomatic improvement is noted. If there are positive localization cultures, patients can be treated similarly, but would be likely classified as NIH Category II prostatitis given the role of non-traditional uropathogens in CP/CPPS. We consider the addition of alpha-blockers in men with significant urinary symptoms. The recent trial with alfuzosin still demonstrates that some patients derive significant benefit from alpha-blockers despite the overall lack of efficacy relative to placebo. If the symptoms do not improve significantly, we refer the patient to the physiotherapists for pelvic floor biofeedback. Recent literature on myofascial trigger points may allow for better standardization, efficacy and study design. In the clinical setting, many men with CP/CPPS have tenderness in several pelvic muscles, which refers to the common chronic pain sites such as the penis or perineum. Subsequent follow-up on these men in small series and in the author's experience reveals that pelvic floor biofeedback offers clinically significant symptom improvement.

Article highlights.

• Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent and burdensome syndrome resulting in chronic pelvic pain, ejaculatory dysfunction, urinary symptoms and a diminished quality of life.

• The Meares–Stamey localization cultures separate this entity from chronic bacterial prostatitis (CBP).

• Recent data provided by a well-designed randomized controlled trial shows that alpha-blockers had no statistical benefit over placebo.

• Most pharmacotherapies lack randomized, controlled studies to verify their efficacy in CP/CPPS patients. However, fluoroquinolones are still considered first-line treatment for men with CP/CPPS.

• Despite this, a symptom-based approach with targeted pharmacotherapy may be the best management.

• Pelvic floor biofeedback offers some promise for effective therapy, but larger trials are needed to substantiate its efficacy.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Notes

This box summarizes key points contained in the article.