Treatment of Nonbacterial Prostatitis: What’s New?



Fig. 7.1
UPOINT structure with the six domains



Successively, due to the high prevalence of sexual dysfunction in men with urological chronic pelvic pain syndrome, Magri et al. proposed the addition of a sexual dysfunction domain in regard to symptom correlation to the conventional UPOINT system (UPOINT-S) [13].

In another study, 162 men were assessed using UPOINT criteria and after adding the sexual dysfunction domain. Using multiple regression analysis UPOINT(S) criteria were then compared to quality of life, as measured by the SF-36® health outcome survey and Chronic Prostatitis Symptom Index. The total number of UPOINT(S) domains correlated with SF-36 and Chronic Prostatitis Symptom Index scores. Using regression analysis the two significant predictors of SF-36 scores were the psychosocial and sexual domains. Men with sexual dysfunction had significantly worse quality of life than men without the condition. Authors’ conclusion was that adding a sexual dysfunction domain to UPOINT may help improve quality of life in men treated for urological chronic pelvic pain syndrome [14].

More recently, the US NIH/NIDDK launched and funded the Multidisciplinary Approach to Pelvic Pain (MAPP) research consortium program, aimed to better understand the pathophysiology of urological chronic pelvic pain syndromes (UCPPSs), to inform future clinical trials and improve clinical care. The primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multisite, longitudinal observational study, including biweekly Internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms, and psychosocial factors to evaluate men and women with UCPPS. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting-state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Another objective of MAPP is to achieve phenotyping of CPPS patients that could lead to individualized treatment strategies [15].

Based on this innovative classification system, there is growing evidence for advantage of an integrated team approach to assess and manage PPS patients. This is most likely to occur in specialized centers.

As a result of the multifactorial origin of PPS, one reason for treatment failure in some large randomized placebo-controlled trials may be the heterogeneity of the patient population. A prospective series of phenotypically directed treatment for PPS has shown significant improvement of symptoms and QoL [16]. Monotherapeutic strategies for the treatment of PPS may fail; therefore, most patients require multimodal treatment aimed at the main symptoms, taking comorbidity into account. In the past 10 years, results from RCTs have led to advances in standard and novel treatment options.



7.2.2 Treatment Modalities


Table 7.1 lists different therapeutic options according to UPOINT domains.


Table 7.1
Therapeutic options according to UPOINT domains




























UPOINT description

Suggested therapies

Urinary

NIH-CPSI urinary score >4

Obstructive voiding symptoms

Bothersome urgency, frequency, and/or nocturia

Elevated post-void residual

Antimuscarinics

α-Blockers

Psychosocial

Clinical depression

Evidence of maladaptive coping

Anxiety/stress

Counseling

Cognitive behavioral therapy

Antidepressants

Anxiolytics

Organ specific

Specific prostate tenderness

Leukocytosis in prostatic fluid

Hematospermia

Extensive prostatic calcification

α-Blockers

5-α-Reductase inhibitors

Phytotherapy

Prostate massage

Infection

Gram-negative bacilli or enterococci localized to prostatic fluida

Documented successful response to antimicrobial therapy

Antimicrobials

Neurologic/systemic conditions

Clinical evidence of central neuropathy

Pain beyond pelvis

Irritable bowel syndrome

Fibromyalgia

Chronic fatigue syndrome

Neuromodulators

Specific therapies for associated conditions

Tenderness of skeletal muscles

Palpable tenderness and/or painful muscle spasm or trigger points in abdomen and/or pelvic floor

Focused pelvic physiotherapy

General physiotherapy

Exercises


Adapted from Nickel [35]

NIH-CPSI National Institutes of Health Chronic Prostatitis Symptom Index, UPOINT Urinary, Psychosocial, Organ specific, Infection, Neurologic/systemic, and Tenderness

aExclude patients with clinical category I or II prostatitis


7.2.2.1 α-Blockers


α-Blockers act on CP/CPPS by relieving the smooth muscle spasm within the bladder neck and prostatic urethra, which eases urinary voiding. This class of drugs can be recommended as first-line medical therapy, particularly in α-blocker-naive men with moderately severe symptoms who have relatively recent onset of symptoms. α-Blockers cannot be recommended in men with long-standing CP/CPPS who have tried and failed α-blockers in the past.

Ten placebo-controlled RCTs (n = 58–272) were identified that evaluated alpha-adrenergic antagonists (tamsulosin [17, 18], alfuzosin [19, 20], doxazosin [21, 22], terazosin [23, 24], and silodosin [25]) in CBP and CP/CPPS.

The majority of the studies (n = 8) showed positive results, with significant differences vs. placebo in improving NIH-CPSI total, urinary symptom, pain, and/or QoL scores or in scores using other validated symptom scoring tools.

However, there was heterogeneity in primary end points, patient eligibility criteria (e.g., previous exposure to alpha-blockers), and trial duration (6 weeks–6 months). A recent systematic review and network meta-analysis of alpha-blocker RCTs found significant differences vs. placebo in improving total, pain, voiding, and QoL NIH-CPSI scores [26]. However, another recent systematic review questioned the clinical significance of these reductions [27]. Major limitations with regard to previously published studies were that two of the larger, placebo-controlled trials that evaluated tamsulosin (n = 196) [17] and alfuzosin (n = 272) [20] failed to show any significant difference in total NIH-CPSI scores, the only outcome achieving statistical significance being the score for ejaculation on the Male Sexual Health Questionnaire (p = 0.04) in the alfuzosin trial. Possible reasons include the short treatment duration (≤12 weeks) and/or inclusion of refractory patients with previous exposure to alpha-blockers.


7.2.2.2 Antibiotic Therapy


Empirical antibiotic therapy is widely used because some patients have improved with antimicrobial therapy.

To date there are only three randomized controlled trials which assessed ciprofloxacin [28], levofloxacin [29], and tetracycline hydrochloride [30] vs. placebo in CP/CPPS patients. Although symptom improvement was observed, these studies failed to show a statistically significant improvement in NIH-CPSI total score from baseline to 6 weeks in a CP/CPPS population. More promising results were observed in a comparison of tetracycline hydrochloride vs. placebo, with significant differences in NIH-CPSI scores and bacterial eradication rates; however, patient numbers were small (n = 48) [30].

Combination therapy of antibiotics with α-blockers has shown even better outcomes in network meta-analysis. Despite significant improvement in symptom scores, antibiotic therapy did not lead to statistically significant higher response rates [31]. In addition, sample sizes of the studies were relatively small, and treatment effects were only modest and most of the time below clinical significance. It may be speculated that patients profiting from treatment have had some unrecognized uropathogens. If antibiotics are used, other therapeutic options should be offered after one unsuccessful course of a quinolone or tetracycline antibiotic over 2 weeks.


7.2.2.3 Pain Pharmacotherapies


Anti-inflammatory agents are considered the second line of pharmacotherapy for pain symptoms, along with α-adrenergic receptor antagonists (α-blockers) for urinary symptoms [32]. A 2009 randomized control trial evaluated celecoxib in CP/CPPS patients, with a statistically significant decrease in NIH-CPSI total (p < 0.015), pain (p < 0.006), and QoL (p < 0.032) scores after 2, 4, and 6 weeks; however, the effects were limited to the short duration of therapy [33].

Furthermore, two recent meta-analyses on anti-inflammatory therapy show mixed conclusions; one reported that NSAIDs were 80 % more likely to achieve a favorable response than placebo (n = 190, relative risk [RR]: 1.8; 95 % confidence interval [CI]: 1.2–2.6), based on the combination of three trials evaluating rofecoxib, celecoxib, and a corticosteroid [26]. The second analysis, based on only the rofecoxib and celecoxib trials, concluded that no significant differences in efficacy could be ascertained for NSAIDs vs. placebo [27]. Overall, a moderate treatment effect has been shown for anti-inflammatory drugs, but larger studies are needed for confirmation, and long-term side effects have to be taken into account.

Opioids produce modest pain relief in some patients with refractory PPS, although there are limited data on the long-term efficacy of opioids in non-cancer pain. Opioid treatment carries the risk of side effects, reduced QoL, addiction, opioid tolerance, and opioid-induced hyperalgesia [34]. Urologists should use opioids for PPS only in collaboration with pain clinics and together with other treatments.

A randomized control trial evaluated pregabalin (n = 218) vs. placebo (n = 106) in the CP/CPPS population. Compared with the placebo group, patients in the pregabalin arm experienced reductions in the NIH-CPSI total score and subscores (p < 0.05). However, pregabalin therapy for 6 weeks was not superior to placebo in the rate of a 6-point decrease in the NIH-CPSI total score [35].


7.2.2.4 5-Alpha-Reductase Inhibitors


The evidence base for the use of 5-alpha-reductase inhibitors in CP/CPPS is limited, with only three small (n = 41–76) RCTs identified, which evaluated finasteride [3638]. The first study showed that finasteride reduced pain and voiding symptoms vs. baseline; however, no statistically significant differences vs. a small and non-comparable control group were observed, which was likely due to lack of power. The second study compared finasteride with Serenoa repens (saw palmetto) and showed that patients treated with finasteride had a significant and enduring improvement (1-year trial duration) in NIH-CPSI total and pain domains, but not for urinary symptoms, when compared with baseline. However, the trial size (n = 64) and lack of a placebo arm are significant warnings when interpreting the results of this study. A third study showed better outcomes, via measurements of subjective overall assessment and NIH-CPSI scores, for finasteride vs. placebo, but the results were not statistically significant.

The REDUCE study prospectively examined the effect of dutasteride vs. placebo in men with prostatitis-like pain (defined as NIH-CPSI pain subscore ≥ 5) and prostatitis-like syndrome (perineal or ejaculatory pain plus NIH-CPSI pain subscore ≥ 4) by evaluating NIH-CPSI scores at baseline and throughout the study (every 6 months for 4 years). NIH-CPSI total score decreased significantly at 48 months in the dutasteride group vs. placebo in men with prostatitis-like pain (n = 678, p < 0.0001) and with prostatitis-like syndrome (n = 427, p = 0.03). In addition, there were significantly more responders (defined as improvement of ≥ 4 units and ≥ 6 units in total CPSI score) with dutasteride vs. placebo for both prostatitis subgroup populations assessed. The REDUCE study was not primarily designed as a CP/CPPS treatment trial, but the significant reductions in NIH-CPSI scores compared with placebo in a relatively large patient cohort (n = 1,105) with prostatitis-like pain or syndrome suggest that use of 5-alpha-reductase inhibitors in older (aged ≥ 50 years) patients with PSA levels >2.5 ng/ml (for those aged 50–60 years) or > 3.0 ng/ml (those aged >60 years) may be of clinical benefit [39].


7.2.2.5 Phytotherapy


Different studies assessed the effect of phytotherapy in CP/CPPS. Saw palmetto, pollen extracts, and pentosan polysulfate showed some improvement of pelvic pain in a few small studies [40]. Specifically, an adequately powered randomized placebo-controlled study of Cernilton showed clinically significant symptom improvement over a 12-week period in inflammatory PPS patients (NIH cat. IIIa) [41]. The effect was mainly based on an important effect on pain. Significant differences between another pollen extract (Prostat/Poltit) and placebo were demonstrated in a small (n = 60) trial, but a validated tool for symptom scoring was not used [42]. Quercetin, a polyphenolic bioflavonoid with documented antioxidant and anti-inflammatory properties, improved NIH-CPSI scores significantly in a small RCT [43]. In contrast, treatment with saw palmetto, most commonly used for benign prostatic hyperplasia, did not improve symptoms over a 1-year period [36]. In a systematic review and meta-analysis, patients treated with phytotherapy were found to have significantly lower pain scores than those treated with placebo [26]. In addition, the overall response rate in network analysis was in favor of phytotherapy (RR: 1.6; 95 % CI: 1.1–1.6). A prospective, comparative trial provides additional evidence that phytotherapy offers symptom improvement in inflammatory CP/CPPS, with significant changes in symptoms from baseline observed for Profluss® (Serenoa repens, selenium, and lycopene) [44]. However, CP/CPPS patients treated with Serenoa repens reported no appreciable long-term improvement in NIH-CPSI scores in a 1-year comparative study vs. finasteride [36]. Recently the results of a randomized controlled phase III study assessing the safety and efficacy of pollen extract in association with vitamins in males with CP/CPPS were published. Participants were randomized to receive oral capsules of phytotherapeutic agent (two capsules every 24 h) or ibuprofen (600 mg, one tablet three times a day) for 4 weeks. At the follow-up examination (following 1 month of treatment), in the phytotherapeutic group, 31/41 patients (75.6 %) reported an improvement in quality of life, defined as a reduction of the NIH-CPSI total score by ≥25 %, compared with 19/46 (41.3 %) in the control group (p = 0.002) [45]. However, this topic has been discussed in detail based on published evidence in the next chapter of this book.

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Jul 17, 2017 | Posted by in UROLOGY | Comments Off on Treatment of Nonbacterial Prostatitis: What’s New?

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