a-Blockers for the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Update on Current Clinical Evidence

Treatment Update

TreaTmenT UpdaTe a-Blockers for the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Update on Current Clinical Evidence J. Curtis Nickel, MD, FRCSC, Naji Touma, MD Kingston General Hospital, Kingston, Ontario, Canada The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is multifactorial, making its treatment difficult. Multimodal therapy including a-adrenergic antagonists (a-blockers), anti-inflammatory agents, and other pain treatments may provide optimal management for CP/CPPS. Although a-blockers are the most prescribed drugs for patients with CP/CPPS, not all studies support their efficacy. A recent meta-analysis of small trials suggested that treatment with a-blockers, possibly in combination with antibacterial agents, is efficacious in relieving symptoms. Third-generation a1A blockers (silodosin, tamsulosin) may provide efficacy as well as reduced cardiovascular side effects. Future research should aim to identify potential biomarkers associated with treatment response. [ Rev Urol. 2012;14(3/4):56-64 doi: 10.3909/riu0557] ® © 2013 MedReviews , LLC Key words Adrenergic alpha-1 receptor antagonists • Tamsulosin • Silodosin • Alfuzosin • Prostatitis C hronic prostatitis (CP) is the most common urologic diagnosis in men younger than 50 years and is also common in men over 50 years.1 In 1995, to improve the diagnosis and treatment of this disorder, the National Institutes of Health (NIH) Prostatitis Collaborative Network undertook to define and classify the various forms of CP.2,3 NIH Category III disease, or nonbacterial CP/chronic pelvic pain syndrome (CP/CPPS), accounts for at least 90% of all cases of prostatitis, and its symptoms can affect up to 10% of men of all ages in North America.4-6 CP/CPPS is a debilitating syndrome that has a serious and significant effect on a patient’s quality of life (QoL), affecting 56 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0557.indd 56 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update both mental and physical health.3,7 Moreover, the medical costs of CP/CPPS are considerable and have been estimated to be higher than the costs associated with rheumatoid arthritis, peripheral neuropathy, or lower back pain.8 The main symptom of CP/CPPS is urogenital pain or discomfort, particularly pain related to ejaculation, possibly attributable in part to painful smooth muscle contrac- consensus among health care practitioners regarding the most beneficial therapeutic approach. The medical treatments most often prescribed for men with CP/CPPS include antibiotics, α1-adrenergic antagonists (α1-blockers), antiinflammatory agents, pain medications (analgesics and/or neuromodulators), and various combinations of these agents. Treatments of CP/CPPS are gener- The etiology of CP/CPPS is multifactorial, and few therapies have shown significant efficacy in reducing CP/CPPS-specific symptoms in randomized, double-blind, placebo-controlled trials. tion.3 CP/CPPS also can be characterized by urinary symptoms that are irritative (storage) and obstructive (voiding).9 Although CP/CPPS often is accompanied by prostate inflammation, the clinical relationship between inflammation and prostatitis pain remains unclear. The etiology of CP/CPPS is complex and has not been fully elucidated. It is thought to be triggered by a variety of events, including previous infection, trauma, voiding dysfunction, allergic reactions, and/or a neuromuscular dysregulation in the pelvic floor or perineum.10,11 Current Treatment Strategies and the Role of a1-Blockers Successful management of CP/CPPS is a challenge for the treating physician; men with this disorder not only experience chronic genitourinary pain, but also may have other urinary symptoms and sexual dysfunction. The etiology and pathogenesis of CP/CPPS are multifactorial, and few therapies have shown significant efficacy in reducing CP/CPPS-specific symptoms in randomized, doubleblind, placebo-controlled trials. The weakness of the evidence has resulted in a lack of treatment ally designed to mitigate specific symptoms that are either reported by the patient or identified during urological examination, with the goal of improving overall QoL. The Chronic Prostatitis Cohort Study, a prospective longitudinal study by the US NIH Chronic Prostatitis Collaborative Research Network (CPCRN) of men with CP/CPPS, found that more than 40% of the men in the study had received previous treatment with a1-blockers.12 Although a1-blockers are the most commonly stud- increased urinary flow and decreased urinary obstruction.13 The benefits of a-adrenergic blockade in LUTS also may be associated with the inhibition of neurogenic inflammatory responses. In the laboratory, experiments with alfuzosin in a rat model of urinary tract inflammatory processes15 have shown that exposure to this a1-adrenoceptor antagonist reduced neurogenic inflammation; it is thought that the treatment blocks the effects of elevated substance P in TRPV1-expressing primary sensory neurons and decreases the number of c-fos– immunoreactive cells, an indicator of inflammation and pain in animal models.16 Other data from an animal model suggested that a1A–subtype-specific blockage of afferent nerves in the bladder may alleviate bladder overactivity and increase bladder capacity.17 Mechanisms by which a1-adrenergic antagonists may provide pain relief in patients with CP/CPPS are less clear. Potential pathways for treatment include the improvement of voiding dysfunction that may be propagating the pain cycle, Treatments of CP/CPPS are generally designed to mitigate specific symptoms. ied drug class for patients with CP/CPPS, there is little highlevel evidence supporting this treatment approach.4 The use of α1-blockers in CP/CPPS is primarily based on their proven efficacy in the treatment of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH).13 LUTS are also common in patients with CP/CPPS.9,14 The mechanism by which a1-adrenergic blockade is useful in managing LUTS is believed to be largely related to the relaxation of prostate, urethra, and bladder neck smooth muscle, ultimately resulting in by blocking the a-receptors in the peripheral or central nervous system to alleviate long-term pain,18 possibly through the modulation of reflex arcs via spinal cord a1-adrenergic receptor blockade.13 Clinical Evidence Evaluating the Use of a1-Blockers A number of clinical studies have provided evidence of the benefits of a1-blockers in CP/CPPS, but the strength of the evidence varies with the study design.11,19-27 For example, some were pilot studies that lacked Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 57 40041700002_RIU0557.indd 57 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update continued a placebo control, or their randomization strategy or study design was questionable.24,25 Other trials used instruments that were not validated to assess symptom improvement in patients with CP/CPPS; as a result, these trials were not included in this article.19,20,28,29 Many other trials of a-blockers in CP/CPPS have been small,21-23 and some have shown a lack of efficacy in certain cases because of insufficient statistical power to detect potential treatment benefits. Two randomized, double-blind, placebo-controlled trials undertaken by the CPCRN of a1-blockers in men with CP/CPPS—an underpowered study with tamsulosin and/or ciprofloxacin30 and a wellpowered study of alfuzosin31— failed to show efficacy in reducing symptoms. Overall, we identified eight placebo-controlled studies that have evaluated the treatment benefit of a1-blockers in CP/CPPS with a contemporary validated instrument (Table 1). The NIH Chronic Prostatitis Symptom Index (NIH-CPSI) is a validated nineitem instrument for the assessment of CP/CPPS-related pain, urinary symptoms, and change in QoL,3,32 and it has been used as the primary efficacy endpoint in the majority of recent clinical trials.4 The inconsistent results and lack of large data sets supporting the use of any specific treatment for CP/CPPS led Anothaisintawee and colleagues to conduct a systematic review and network meta-analysis.4 The aim of the meta-analysis was to assist in the identification of effective therapies by synthesizing the available data and creating indirect comparisons. Meta-analysis using direct comparisons was not possible based on the large number of available treatment options and the small number of published studies.4 Data were compiled for total symptom scores, pain, voiding, and QoL scores following treatment with a1-blockers, other treatments, or placebo, and response rates associated with the available treatments were compared; 21 of 25 studies used the NIH-CPSI to assess symptoms.4 Based on the scores for total treatment, pain, voiding, and QoL, the network meta-analysis suggested that the use of a1-blockers or a combination of a1-blockers plus antibiotics were the most effective treatment strategies. Although the efficacy of combined therapy appeared to be greater than that of monotherapy, the quality of the trials evaluating α1-blocker monotherapy was superior.4 Although these data are of interest, the limitations of metaanalysis must be considered, including the potential for publication and selection bias during data selection and the disadvantages associated with combining data from stud- and diverse study designs. Of eight randomized, placebo-controlled trials we identified that have used the NIH-CPSI, two were phase III studies, including a 6-week study of tamsulosin, 0.4 mg/d, and ciprofloxacin30 and a 12-week study of alfuzosin, 10 mg/d.31 The other placebo-controlled studies were phase II or pilot studies of silodosin, tamsulosin, alfuzosin, doxazosin, or terazosin. According to a summary of data from these trials, the benefits of therapy defined as either the treatment effect (Figure 1) or the percentage of responders (Figure 2) have varied widely. To our knowledge, comparative studies of a1-blockers in patients with CP/CPPS have not been conducted. Many earlier studies evaluated the use of second-generation a-adrenergic blockers (ie, doxazosin, terazosin) nonselective for a specific The third-generation [alpha-blockers] are reported to have a higher affinity for the a1A-receptor, which is prevalent in human prostate tissues. Selectivity for the receptors in the prostate results in fewer adverse events mediated by a1B-receptor stimulation in the vasculature. . . a1-Blockers may provide overall improvement of CP/CPPS-associated symptoms, as assessed by NIH-CPSI total scores, especially in a1-blocker–naive patients with acute symptoms. ies with a high degree of variability during network meta-analysis. A closer review of the a-blocker trials in patients with CP/CPPS is worthwhile to gain a better understanding of outcomes from the primary studies of a-blockers in CP/CPPS analyzed in the metaanalysis, to consider more recently published data, and to discern differences among the studies. Notable differences include duration of treatment (ranging from 6 weeks to 6 months; Table 1), the use of a placebo washout or run-in period, the inclusion of diverse study populations (ie, treatment-refractory groups, treatment-naïve groups, and acute vs long-term symptoms), receptor subtype, whereas more recent studies have evaluated the third-generation uroselective agents tamsulosin and silodosin in patients with CP/CPPS.26,27 The third-generation agents are reported to have a higher affinity for the a1A-receptor, which is prevalent in human prostate tissues.13,33 Selectivity for the receptors in the prostate results in fewer adverse events mediated by a1B-receptor stimulation in the vasculature. For example, competitive binding experiments have found that the selectivity of silodosin is more than 100 times greater for the a1A than the a1B subtype, and that of tamsulosin is almost 10-fold greater with a moderate affinity for the 58 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0557.indd 58 12/02/13 2:28 PM 40041700002_RIU0557.indd 59 6 months 14 weeks Single-blind 6 weeks 6 weeks 6 months 12 weeks 12 weeks 6 months Duration of Treatment Double-blind Double-blind Double-blind NR Double-blind Double-blind Double-blind Blinding 25.1 6 7.1 27.2 6 7.7 Placebo 23.0 Placebo Terazosin 1-5 mg/d 26.0 26.4 6 4.9 26.2 6 6.5 24.6 6 6.2 25.0 6 5.1 26.0 6 6.3 26.8 6 5.9 27.9 6 6.2 23.8 6 6.3 25.1 6 5.9 23.1 6 1.8 22.9 6 1.2 23.3 6 6.2 22.5 6 5.6 Mean 6 SD Alfuzosin 10 mg/d Tamsulosin 0.4 mg/d Placebo Tamsulosin 0.4 mg/d Placebo Silodosin 4 mg/d Silodosin 8 mg/d Placebo Alfuzosin 10 mg/d Placebo Doxazosin 4 mg/d Placebo Tamsulosin 0.2 mg/d Placebo Treatments 210.2 b 214.3b 23.8 29.9 NR NR 24.4 6 6.3 23.4 6 5.0 212.1 6 9.3 210.2 6 8.8 28.5 6 7.2 27.1 6 9.0 26.5 6 8.5 212.4b 21.0b 27.5 6 1.9 24.0 6 2.3 Change From Baseline Mean 6 SD .01 .01 .04 . .2 , .05 .70 .02 .59 , .01 P Value CI, confidence interval; NR, not reported. a Data not shown for the group treated with a combination of doxazosin, ibuprofen, and thiocolchicoside (n 5 30).11 b Difference in mean score at baseline and end of treatment. c Not all treatment groups are listed; a total of 196 patients were studied using a 2 3 2 factorial analysis plan that also included two groups randomized to ciprofloxacin alone (n 5 49) or a combination ciprofloxacin/tamsulosin (n 5 49).30 d Only randomized treatment arms are shown. N 5 86 Cheahm PY et al22 N 5 98c Alexander RB et al30 N 5 40d N 5 60a Tuğcu V et al11 Mehik A et al21 N 5 272 Nickel JC et al31 N 5 57 N 5 148 Nickel JC et al27 Nickel JC et al23 N 5 100 Randomized Chen Y et al26 Study Baseline Scores Randomized Placebo-Controlled Clinical Studies That Evaluated the Use of a-Blockers for Treatment of CP/CPPS Using NIH-CPSI Score as the Primary Efficacy Outcome TABLe 1 a-Blockers for Treatment of CP/CPPS: Clinical Update Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 59 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update continued 12 11.4 Treatment Effect 10 8 6.1 6 4.2 4 1.8 2 1.0 0.6 0 4.1 3.6 3.5 Tamsulosin 0.2 mg/d Chen et al26 Silodosin 4 mg/d Silodosin 8 mg/d Alfuzosin 10 mg/d Nickel et al31 Nickel et al27 Doxazosin Tamsulosin Tamsulosin 4 mg/d 0.4 mg/d 0.4 mg/d Tuğcu et ala,11 Alexander et alb,30 Nickel et al23 Alfuzosin 10 mg/d Terazosin 1–5 mg/d Mehik et al21 Cheah et al22 Figure 1. Treatment effect associated with the use of α-blockers measured according to the National Institutes of Health Chronic Prostatitis Symptom Index during randomized, placebo-controlled clinical studies of patients with chronic prostatitis/chronic pelvic pain syndrome. Treatment effect defined as the difference in change from baseline between active treatment and placebo. aData not shown for a group treated with a combination of doxazosin, ibuprofen, and thiocolchicoside (n 5 30).11 bNot all treatment arms are shown; a total of 196 patients were studied using a 2 3 2 factorial analysis plan that also included a ciprofloxacin group (n 5 49) and combination ciprofloxacin/tamsulosin group (n 5 49).30 a1D-subtype receptor.14 In those who receive treatment with second-generation a-adrenergic antagonists, postural hypotension and other cardiovascular side effects may be reduced by initiating treatment at the lowest starting dose, administering treatment at bedtime, and closely monitoring blood pressure in patients who are receiving concomitant treatment with antihypertensive agents. Tamsulosin At this time, three prospective, placebo-controlled trials have evaluated the effects of the third-generation a-adrenergic antagonist tamsulosin as measured by the NIH-CPSI in patients with CP/CPPS.23,26,30 The most recent trial by Chen and colleagues was the first to evaluate the longer-term effects of an α1-blocker in a prospective, randomized study.26 This placebo-controlled, prospective phase III study was conducted in 100 Chinese men with a $ 3-month history of pain or discomfort in the pelvic region who had not received prior treatment with a1-blockers.26 In this study, patients were randomized to treatment for 6 months with a low dose of tamsulosin (0.2 mg) or placebo to determine the effects of tamsulosin on symptom relief, as measured by change in NIH-CPSI during treatment and over a 2-year follow-up period.26 After 3 and 6 months of treatment, response rates were found to be significantly greater in patients who received active treatment compared with those who received placebo (P , .05). Although significant differences remained between the groups 6 months after treatment cessation, these differences slowly dissipated between 12 and 24 months after the discontinuation of the α-blocker, suggesting the need for chronic treatment.26 A review of the NIH-CPSI subscale data showed that the treatment benefit seen in this study appeared to be largely attributable to improvement in the pain score. An earlier placebo-controlled, 6-week phase II trial of tamsulosin conducted in 58 patients also found significant benefits associated with the use of tamsulosin in patients with a $ 3-month history of moderate to severe CP/CPPS.23 After a 2-week washout period, tamsulosin, 0.4 mg, was administered daily for 6 weeks, and the NIH-CPSI was used to measure efficacy at day 15 and day 45.23 The definition of response was set high in this study compared with others; response was defined as a $ 6-point decrease in NIH-CPSI score compared with baseline, a 25% decrease in total NIH-CPSI score compared with baseline (perceptible improvement), or a 50% decrease from baseline.23 Notably, patients with more severe symptoms at baseline experienced the most significant improvement.23 Whereas patients with less severe pain scores at baseline did not experience significant improvement from baseline at day 45, patients with more severe pain 60 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0557.indd 60 12/02/13 2:28 PM Terazosin Tamsulosin Doxazosin Silodosin Alfuzosin Nickel et al31 Mehik Tuğcu Nickel Chen Alexander Nickel Cheah e,11 2011d,27 et alc,26 et alb,36 et al23 et ala,22 et alf,21 et al a-Blockers for Treatment of CP/CPPS: Clinical Update Placebo Terazosin Placebo Tamsulosin Placebo NIH-CPSI active GRA active NIH-CPSI placebo GRA placebo Tamsulosin Placebo Tamsulosin Placebo Silodosin Placebo Doxazosin Placebo Alfuzosin Placebo Alfuzosin 0 10 20 30 40 Percent of Responders 50 60 70 Figure 2. Percentage of responders during randomized clinical trials of α-blockers in patients with chronic prostatitis/chronic pelvic pain syndrome. aP 5 .03 for terazosin vs placebo at 38 weeks.22 bNot all treatment arms are shown; a total of 196 patients were studied using a 2 3 2 factorial analysis plan that also included a ciprofloxacin group (n 5 49) and combination ciprofloxacin/tamsulosin group (n 5 49).30 cP , .05 for tamsulosin vs placebo at 12 months.26 d P , .025 for GRA of silodosin vs placebo at 3 months.27 eData not shown for a group treated with a combination of doxazosin, ibuprofen, and thiocolchicoside (n 5 30).11 fP 5 .02 for alfuzosin vs placebo at 6 months (note: placebo response not reported).21 GRA, Global Response Assessment; NIH-CPSI, National Institutes of Health Chronic Prostatitis Symptom Index. Definitions of Response: NIH-CPSI: Nickel et al3: $ 4-point decrease from baseline to 12 weeks; Mehik et al21: 33% decrease from baseline in total NIH-CPSI score; Cheah et al,22 Tuğcu et al11: score of # 2 on the NIH-CPSI QoL subscale; Nickel et al23,27: $ 6-point decrease in total score; Chen et al26: $ 4-point decrease from baseline to 12 months. GRA: Nickel et al,3,27 Alexander et al30: markedly or moderately improved on 7-point scale. scores before treatment experienced significant improvement compared with placebo (P 5 .02).23 Among all 57 men who had undergone treatment evaluations, regardless of baseline NIH-CPSI scores, significant improvement was observed at day 45 in total NIH-CPSI score, urinary symptoms, and QoL.23 On day 15, no differences were observed between groups in total NIH-CPSI score, urinary symptoms, or QoL. The lack of an early response might be explained by an inadequate washout period before treatment began or by a response that developed slowly over time.23 By contrast, Alexander and colleagues reported no significant benefits associated with the use of ciprofloxacin or tamsulosin in men with a longstanding history of treatment for refractory CP/CPPS.30 In their phase III study, patients were randomly assigned to 6-week treatment with tamsulosin, 0.4 mg daily, ciprofloxacin, 500 mg twice daily, tamsulosin plus ciprofloxacin, or placebo. The severity of symptoms was measured at 6 weeks, 9 weeks, and 12 weeks using the NIHCPSI.30 In this study, no significant improvement was found in the primary outcome variable, defined as change from baseline in NIH-CPSI total score at 6 weeks for any groups, including those who received tamsulosin.30 The lack of benefit may have been attributable in part to the fact that the study participants had longstanding symptoms refractory to previous treatments, including α1-blockers; the 2 3 2 factorial study design that included patients treated with antibiotics; and/or to an underpowered study design, as the number of patients per treatment group (eg, direct comparison of tamsulosin only vs placebo) was low.30 Other possible explanations may be the lack of a placebo run-in period, an inadequate duration of treatment in this study, or an inadequate duration of follow-up, as the effects of tamsulosin may develop slowly over time as suggested by the results of other studies.23,26 Alfuzosin Two placebo-controlled trials have reported on the efficacy of alfuzosin, a second-generation a-adrenergic antagonist, in men Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 61 40041700002_RIU0557.indd 61 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update continued with CP/CPPS, with conflicting results. The study groups exhibited important differences with regard to the duration of symptoms.21,31 The more recent of the two studies was the largest prospective evaluation of an a1-blocker in CP/CPPS, conducted in 272 men presenting with the symptoms of CP within the past 2 years who were naive to a1-blocker treatment.31 Eligible patients were randomly assigned to receive 12-week treatment with alfuzosin, 10 mg, or placebo and were then evaluated at week 12 for the primary outcome variable, a $ 4-point improvement as measured by the reduction in NIH-CPSI score from baseline to 12 weeks.31 No significant treatment benefits were found in patients treated with alfuzosin, 10 mg (Table 1). A number of secondary outcome variables also were analyzed, including pain, QoL, depression and anxiety, and sexual health, with no significant differences found between the treatment groups.31 These results contrast with those of the earlier, smaller placebo-controlled study (n 5 40) of alfuzosin in patients with a $ 3-month history of CP/CPPS, in which 6-month therapy with alfuzosin, 10 mg/d, provided modest decreases in NIH-CPSI total score compared with placebo.21 It is possible that longer duration (. 12 weeks) of treatment with alfuzosin would be necessary to obtain benefits in a1-blocker– naive patients with CP/CPPS. In addition, patients with more acute symptoms may be more responsive to treatment with a1-blockers.31 Silodosin Recently published data from a large phase II study of the thirdgeneration agent silodosin suggested that patients with CP/CPPS derive significant benefits from treatment with this highly selective a1A-blocker.27 The silodosin study included 151 men with a $ 3-month history of pain in the pelvic region who were naive to treatment with a1-blockers.27 After a 4-week washout period, eligible patients were randomly assigned to treatment with silodosin, 4 mg/d, silodosin, 8 mg/d, or placebo for up to 12 weeks.27 Two different doses of silodosin were chosen to evaluate the possibility of dosedependent effects. The higher dose was chosen based on the established silodosin dosage for treatment of patients with BPH.27 The primary endpoint in this study was response rate according to change in NIH-CPSI score from baseline to week 12 (Table 1). Response was defined as a $ 6-point decrease in the NIH-CPSI.27 Secondary endpoints included the NIH-CPSI subscale scores, Global Response Assessment (GRA) scale scores, pain medication use, and performance on the short form 12-item (SF-12) health survey.27 At week 12, silodosin, 4 mg, was associated with significantly greater decreases in NIH-CPSI total score compared with placebo.27 Larger decreases from baseline in the total NIH-CPSI score also were noted in the 8-mg dose group compared with placebo at week 12, although the differences were not statistically significant.27 Other significant benefits in patients receiving silodosin, 4 mg, were demonstrated by significantly improved NIHCPSI urinary symptom scores (P 5 .0102), NIH-CPSI QoL scores (P 5 .0099), and SF-12 physical component scores (P 5 .0492) compared with those who received placebo.27 Significant improvement was also noted in measures of global response, defined as “moderately” or “markedly” improved according to a 7-point GRA scale.27 Nearly twice as many patients in the silodosin 4-mg group indicated moderate or marked improvement in the GRA compared with the placebo patients.27 Despite these positive findings, there were no significant differences between treatment groups in the percentage of NIH-CPSI responders (ie, those achieving a reduction in total score $ 6 points). However, the definition of response was stringent compared with most other a-blocker studies, which often defined response as a $ 4-point reduction in total NIH-CPSI. Other a1-Blockers Clinical trials evaluating the effects of treatment with other second-generation a-adrenergic antagonists including doxazosin or terazosin reported positive findings in patients with CP/CPPS.11,26,34 The most recent of these trials evaluated treatment with doxazosin alone, doxazosin in combination with an anti-inflammatory agent and a muscle relaxer, or placebo in treatment-naive patients over a period of 6 months and found that active treatment conferred a significant benefit in total symptom relief that was durable up to 6 months after the cessation of treatment.11 There also was consistent and significant QoL improvement in both active treatment groups that lasted until the end of the study, as well as significantly reduced domain scores for pain and urinary symptoms in treatment-naive patients with CP/CPPS compared with placebo.11 Notably, the benefit of doxazosin alone was similar to that seen with triple therapy with doxazosin, ibuprofen, and thiocolchicoside.11 Similar outcomes were reported in an earlier trial by Cheah and colleagues.22 Treatment-naive men with CP/CPPS received treatment with the a-adrenergic blocker terazosin for 14 weeks. In this trial, significant improvement was seen in the NIH-CPSI total score (P , .001) as well as in pain, 62 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0557.indd 62 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update urinary symptom, and QoL impact scores (P , .05) after 14 weeks of treatment. Response rate after 14 weeks also was significantly better in the terazosin group compared with placebo (P 5 .03).22 In an additional follow-up of patients from this study 6 months later, the investigators found that response rates assessed 24 weeks after the treatment phase (terazosin vs placebo, P 5 .03) were essentially the same as those recorded at the end of treatment.34 The durable response rates, defined as an initial response plus a long-term response despite no treatment for CP/CPPS after the discontinuation of terazosin at week 12, was 44% for active treatment versus 16% for placebo (P 5 .01).34 Conclusions Together these data suggest that a-blocker treatment confers a modest benefit in some patients with CP/CPPS. Despite negative results of two phase III studies, one with alfuzosin and one with tamsulosin, 30,31 other data suggest that α1-blockers may provide overall improvement of CP/CPPSassociated symptoms as assessed by NIH-CPSI total scores, especially in a1-blocker–naive patients with acute symptoms. Data from studies with longer follow-up periods after the cessation of therapy further suggest that lasting symptom improvement may require persistent therapy. Longer treatment periods may be required for treatment effects that develop slowly over time, or simply to compensate for the possibility of inadequate washout periods, which can skew the data in favor of inactive treatment. Consequently, largescale, placebo-controlled studies of longer duration in specifically selected patients (ie, patients with a voiding dysfunction phenotype) are needed to validate the use of these treatments in patients with CP/CPPS. Although it is difficult to determine the reasons for the disparities among studies, the causes most likely relate to differences in the patient populations (eg, differences in duration of CP/CPPS symptoms or use of prior treatments for CP/CPPS), study design (eg, differences in presence of a washout period, duration of treatment, and follow-up periods), and type of a-adrenergic antagonist studied (eg, adrenergic receptor subtype– selective vs nonselective agents). At this time, there is no evidencebased algorithm to support the use of a-blocker therapy according to disease or patient-specific factors. However, available evidence suggests an increased chance of benefit may be related to the presence of storage or voiding LUTS (U phenotype in the UPOINT CP/CPPS classification),35 no prior treatment with a-blockers, no history of a-blocker–refractory symptoms, newly symptomatic patients with CP/CPPS, and an absence of confounding disorders such as pelvic floor dysfunction, which may cause symptoms and be associated with a lack of response. The duration of therapy also may be a predictor of outcomes, as studies of longer treatment durations have reported more positive outcomes compared with studies that had shorter treatment courses. Considering the complex etiology of CP/CPPS, the modest benefits possible with monotherapy with a-adrenergic blockers should not be considered an effective approach for most patients. Rather, a multimodal approach is recommended,35,36 which may include an a-adrenergic antagonist to target an individually identifiable clinical phenotype. Further data are needed to support the choice of therapy based on patient characteristics alone, but choices include a1blockers for patients with voiding problems; antibiotics in those with a history of urinary tract infections; anti-inflammatory agents (including some phytotherapeutic agents) and neuromodulation in patients with pain and/or demonstrable inflammation; and physical therapies for pelvic floor dysfunction.36 It is hoped that future studies will help to individualize treatment by identifying potential clinical or biochemical biomarkers to aid in the identification and selection of patients who will benefit most from the addition of a-blockade to a combination therapy approach. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Collins MM, Stafford RS, O’Leary MP, Barry NJ. How common is prostatitis? A national survey of physician visits. J Urol. 1998;159:1224-1228. Krieger JN, Nyberg L Jr, Nickel JC. NIH consensus definition and classification of prostatitis [letter]. JAMA. 1999;282:236-237. Nickel JC, Alexander RB, Anderson R, et al. Category III chronic prostatitis/chronic pelvic pain syndrome: insights from the National Institutes of Health Chronic Prostatitis Collaborative Research Network studies. Curr Urol Rep. 2008;9:320-327. Anothaisintawee T, Attia J, Nickel JC, et al. Management of chronic prostatitis/chronic pelvic pain syndrome: a systematic review and network metaanalysis. JAMA. 2011;305:78-86. Roberts RO, Jacobson DJ, Girman CJ, et al. Prevalence of prostatitis-like symptoms in a community based cohort of older men. J Urol. 2002;168:2467-2471. Nickel JC, Downey J, Hunter D, Clark J. Prevalence of prostatitis-like symptoms in a population based study using the National Institutes of Health chronic prostatitis symptom index. J Urol. 2001;165:842-845. McNaughton Collins M, Pontari MA, O’Leary MP, et al. Quality of life is impaired in men with chronic prostatitis: the Chronic Prostatitis Collaborative Research Network. J Gen Intern Med. 2001;16:656-662. Calhoun EA, McNaughton Collins M, Pontari MA, et al. The economic impact of chronic prostatitis. Arch Intern Med. 2004;164:1231-1236. Nickel JC. The overlapping lower urinary tract symptoms of benign prostatic hyperplasia and prostatitis. Curr Opin Urol. 2006;16:5-10. Zermann DH, Schmidt RA. Neurophysiology of the pelvic floor: its role in prostate and pelvic pain. In: Nickel JC, ed. Textbook of Prostatitis. Oxford: ISIS Medical Media; 1999:95-105. Tuğcu V, Taşçi AI, Fazlioğlu A, et al. A placebocontrolled comparison of the efficiency of triple- and monotherapy in category III B chronic pelvic pain syndrome (CPPS). Eur Urol. 2007;51:1113-1117. Schaeffer AJ, Landis JR, Knauss JS, et al. Demographic and clinical characteristics of men with chronic prostatitis: the National Institutes of Health Chronic Prostatitis Cohort Study. J Urol. 2002;168:593-598. Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary tract symptoms. Int J Urol. 2008;15:193-199. Michel MC. The pharmacological profile of the a1A-adrenergic antagonist silodosin. Eur Urol Suppl. 2010;9: 486-490. Vol. 14 No. 3/4 • 2012 • Reviews in Urology • 63 40041700002_RIU0557.indd 63 12/02/13 2:28 PM a-Blockers for Treatment of CP/CPPS: Clinical Update continued 15. 16. 17. 18. 19. 20. 21. 22. Geppetti P, Nassini R, Materazzi S, Benemei S. The concept of neurogenic inflammation. BJU Int. 2008;101(suppl 3):2-6. Trevisani M, Campi B, Gatti R, et al. The influence of alpha1-adrenoreceptors on neuropeptide release from primary sensory neurons of the lower urinary tract. Eur Urol. 2007;52:901-908. Yokoyama O, Ito H, Aoki Y, et al. Selective α1Ablocker improves bladder storage function in rats via suppression of C-fiber afferent activity. World J Urol. 2010;28:609-614. Andersson K-E, Gratzke C. Pharmacology of α1adrenoceptor antagonists in the lower urinary tract and central nervous system. Nat Clin Pract Urol. 2007;4:368-378. Neal DE Jr, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology. 1994;43:460-465. Evliyaoğlu Y, Burgut R. Lower urinary tract symptoms, pain and quality of life assessment in chronic non-bacterial prostatitis patients treated with alphablocking agent doxazosin versus placebo. Int Urol Nephrol. 2002;34:351-356. Mehik A, Alas P, Nickel JC, et al. Alfuzosin treatment for chronic prostatitis/chronic pelvic pain syndrome: a prospective, randomized, double-blind, placebocontrolled, pilot study. Urology. 2003;62:425-429. Cheah PY, Liong ML, Yuen KH, et al. Terazosin therapy for chronic prostatitis/chronic pelvic pain 23. 24. 25. 26. 27. 28. 29. syndrome: a randomized, placebo controlled trial. J Urol. 2003;169:592-596. Nickel JC, Narayan P, McKay J, Doyle C. Treatment of chronic prostatitis/chronic pelvic pain syndrome with tamsulosin: a randomized double blind trial. J Urol. 2004;171:1594-1597. Jeong CW, Lim DJ, Son H, et al. Treatment for chronic prostatitis/chronic pelvic pain syndrome: levofloxacin, doxazosin and their combination. Urol Int. 2008;80:157-161. Ye ZQ, Lan RZ, Yang WM, et al. Tamsulosin treatment of chronic non-bacterial prostatitis. J Int Med Res. 2008;36:244-252. Erratum in: J Int Med Res. 2008;36:612. Chen Y, Wu X, Liu J, et al. Effects of a 6-month course of tamsulosin for chronic prostatitis/chronic pelvic pain syndrome: a multicenter, randomized trial. World J Urol. 2011;29:381-385. Nickel JC, O’Leary MP, Lepor H, et al. Silodosin for men with chronic prostatitis/chronic pelvic pain syndrome: results of a phase II multicenter, doubleblind, placebo controlled study. J Urol. 2011;186: 125-131. Lacquaniti S, Destito A, Servello C, et al. Terazosine and tamsulosin in non bacterial prostatitis: a randomized placebo-controlled study. Arch Ital Urol Androl. 1999;71:283-285. Gül O, Eroğlu M, Ozok U. Use of terazosine in patients with chronic pelvic pain syndrome and evaluation by 30. 31. 32. 33. 34. 35. 36. prostatitis symptom score index. Int Urol Nephrol. 2001;32:433-436. Alexander RB, Propert KJ, Schaeffer AJ, et al. Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial. Ann Intern Med. 2004;141: 581-589. Nickel JC, Krieger JN, McNaughton-Collins M, et al. Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome. N Engl J Med. 2008;359:2663-2673. 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. J Urol. 1999;162:369-375. Andersson KE, Lepor H, Wyllie MG. Prostatic alpha 1-adrenoceptors and uroselectivity. Prostate. 1997;30:202-215. Cheah PY, Liong ML, Yuen KH, et al. Initial, longterm, and durable responses to terazosin, placebo, or other therapies for chronic prostatitis/chronic pelvic pain syndrome. Urology. 2004;64:881-886. Shoskes DA, Nickel JC, Kattan M. Phenotypically directed multimodal therapy for chronic prostatitis/ chronic pelvic pain syndrome: a prospective study using UPOINT. Urology. 2010;75:1249-1253. Nickel JC, Shoskes D. Phenotypic approach to the management of the chronic prostatitis/chronic pelvic pain syndrome. Br J Urol Int. 2010;106:1252-1263. MAin PoinTs • Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating syndrome that has a serious and significant effect on a patient’s quality of life, affecting both mental and physical health. • Current treatments for CP/CPPS aim to relieve symptoms, especially urogenital pain. Evidence for the efficacy of a1-blockers is mixed, but on balance, the third-generation agents do appear to relieve prostatitis symptoms in some patients. • Considering the complex etiology of CP/CPPS, the modest benefits possible with monotherapy with a-adrenergic blockers should not be considered an effective approach for most patients. Individualized multimodal therapy, including a1-blockers, anti-inflammatory agents, and/or pain medications (analgesics and/or neuromodulators), continues to be the preferred treatment approach for CP/CPPS. • Future studies are needed to identify biomarkers or other indicators that would help determine the best therapeutic approach for individual patients. 64 • Vol. 14 No. 3/4 • 2012 • Reviews in Urology 40041700002_RIU0557.indd 64 12/02/13 2:28 PM