Patients with benign prostatic hyperplasia (BPH) often complain not only lower urinary tract symptom (LUTS) but also lower abdominal pain and/or perineal discomfort recognized as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We recently reported a correlation only between histological prostatitis and CP/CPPS evaluated by the National Institutes of Health chronic prostatitis symptom index (NIH-CPSI). However, it is well known that patients without inflammatory signs such as pyuria bother about CP/CPPS. Until recently, α1-antagonists and 5α-reductase inhibitors were the primary medications prescribed for BPH in Japan. However, these treatments are not effective in all patients, especially with CP/CPPS. The selective phosphodiesterase type 5 (PDE-5) inhibitor, tadalafil, was approved to treat men with BPH with or without erectile dysfunction in Japan in 2014. The effectiveness and tolerability of tadalafil for this indication has been established in placebo-controlled clinical studies in Asian populations with BPH. In addition, it was shown that PDE-5 inhibitor exerts an anti-inflammatory effect on human myofibroblast prostatic cells, blunting reactions to inflammatory cytokines. Thus, the basic clinical question has arisen of whether tadalafil can cure CP/CPPS symptoms, especially pain, as well as LUTS for patients with BPH. 
In this study, we focus on whether tadalafil is more effective for patients with severe CP/CPPS than others after confirming the efficacy and the relation between pain of CP/CPPS symptoms evaluated by NIH-CPSI and LUTS evaluated by several questionnaires including the International Prostate Symptom Score (IPSS), QOL index and Overactive Bladder Symptom Score (OABSS).

Included in this study were 74 male patients (mean age, 68.2 ± 9.2 years) diagnosed with either moderate or severe BPH, as indicated by a total score of >8 on IPSS. LUTS were assessed by QOL index and OABSS together with IPSS. Maximum flow rate by uroflowmetry as one of objective findings was evaluated at the same time as the questionnaire. Although all patients didn’t complain CP/CPPS, its symptom was also assessed by NIH-CPSI. Patients were excluded if they had been diagnosed with prostate cancer, undergone surgical treatment of the prostate gland, had a urinary tract infection, experienced acute urinary retention within 4 weeks of the screening visit, or had a history or evidence of urethral stricture or renal dysfunction. All patients were instructed to take tadalafil 5 mg orally each morning for 12 weeks. 
Firstly, IPSS was compared between patients with high (>4; high group) and low (<4; low group) of pain subscore of NIH-CPSI at the pretreatment baseline to clarify whether pain among CP/CPPS symptoms is associated with LUTS severity. Secondary, LUTS and CP/CPPS symptoms were compared before and after treatment to evaluate the efficacy of tadafafil. Thirdly, a correlation between the changes of subscore of pain in NIH-CPSI and IPSS during treatment was investigated. Finally, the improvement of IPSS was compared between the high group and the low group of pain subscore of NIH-CPSI.
The study was written informed consent was obtained from all patients and the procedures were approved by the Regional Ethics Committee of our hospital. Data are presented as mean ± standard error. Statistical analysis was performed by Student t-test, Mann-Whitney’s U test and Pearson correlation coefficient. A P-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 24.0 (SPSS Inc., Chicago, IL, USA).

At the pretreatment baseline, pain subscore of NIH-CPSI was high (>4) in 24 of 74 (32.4%) patients. IPSS in the high group of pain subscore of NIH-CPSI was significantly higher (19.6 ± 5.3) than that in the low group (16.6 ± 5.3; P<0.05). 
Regarding the efficacy of tadalafil, IPSS was significantly improved after the treatment as expected (17.6 ± 5.5 vs 12.3 ± 6.7; P<0.001). QOL index (4.7 ± 0.9 vs 3.1 ± 1.7; P<0.001) and OABSS (5.3 ± 2.5 vs 4.3 ± 2.2; P<0.001) were also significantly improved. However, maximum flow rate did not show a significant improvement. NIH-CPSI total score was significantly improved (14.6 ± 6.2 vs 9.3 ± 5.4; P<0.001). Interestingly, a significantly improvement was also found in pain subscore (2.6 ± 3.6 vs 1.2 ± 2.0; P<0.01). 
The change of NIH-CPSI correlated positively with the change of IPSS (Pearson’s correlation 0.652, P<0.001). Furthermore, the change of subscore of pain also correlated positively with the change of IPSS (Pearson’s correlation 0.369, P<0.01) (Figure1). Decreased IPSS in the high group of pain subscore of NIH-CPSI (-8.5 ± 7.1) was significantly greater than that in the low group (-3.0 ± 5.6; P<0.05) (Figure2).

BPH was often associated with histological inflammation, inducing CP/CPPS. CP/CPPS is usually diagnosed by exclusion without histological confirmation. We already reported that NIH-CPSI score for CP/CPPS correlate closely with the degree and severity of inflammation in prostatic tissue in patients with BPH (1). Thus, we place high importance on NIH-CPSI in this study. In the clinical setting, CP/CPPS is usually refractory to medications for BPH. Historically, the standard medical treatment for LUTS in men with BPH included α1-antagonists, 5α-reductase inhibitors and phytotherapy. These agents remain indeed today the mainstay of BPH treatment. However, it was already reported that the efficacy of α1-antagonists and 5α-reductase inhibitors in patients with high grade inflammation of the prostate tissue are poorer than those with low grade inflammation. The basic question is whether LUTS of patients with BPH complaining pain among CP/CPPS symptoms is worse than that of patients without pain. In regard to this point, we can provide a valuable finding that IPSS in the high group of pain subscore of NIH-CPSI was significantly higher than that in the low group. Another question is the efficacy of tadalafil for CP/CPPS symptoms; whether tadalafil can cure CP/CPPS symptoms, especially pain, as well as LUTS for patients with BPH. Fortunately, we could confirm the efficacy of tadalafil for patients with BPH by several questionnaires in this study. Indeed, we clearly showed the improvement of each score of questionnaires including IPSS, QOL index and OABSS. We also showed the improvement of NIH-CPSI by tadalafil. Although it is enough interesting that tadalafil is proven to be effective for CP/CPPS, the more interesting finding is that the change of NIH-CPSI correlated positively with the change of IPSS. Furthermore, we also showed that the change of subscore of pain correlated positively with the change of IPSS. These findings may mean that reducing CP/CPPS symptoms including pain is essential for the treatment for LUTS. Eventually, the most interesting finding in this study is that decreased IPSS in the high group of pain subscore of NIH-CPSI at the pretreatment baseline was significantly greater than that in the low group. It was reported that soluble cyclic guanosine monophosphate plays a key role in the nitric oxide-mediated inhibition of leukocyte rolling, and PDE5 inhibition may reduce atherosclerotic damage and overall inflammation by reducing leukocyte recruitment. Tadalafil was shown to attenuate in vitro the expression of the inflammatory cytokines TNF-α and IL-1βin pulmonary arteries and of TNF-α and IL-8 in endothelial cells (2). Based on these previous reports and our findings, we conclude that tadalafil is sufficiently effective for patients with BPH together with severe CP/CPPS.

In this study, we conclude that tadalafil is sufficiently effective for patients with BPH together with severe CP/CPPS. When patients with BPH complain perineal discomfort and/or pain, tadalafil may be the first choice for the medical treatment.

Mizuno T, Hiramatsu I, Aoki Y, Shimoyama H, Nozaki T, Shirai M, Lu Y, Horie S, Tsujimura A, et al. Relation between histological prostatitis and lower urinary tract symptoms and erectile function. Prostate international 2017, 5(3):119-123
Roumeguère T, Zouaoui Boudjeltia K, Babar S, Nuyens V, Rousseau A, Van Antwerpen P, et al. Effects of phosphodiesterase inhibitors on the inflammatory response of endothelial cells stimulated by myeloperoxidase-modified lowdensity lipoprotein or tumor necrosis factor alpha. Eur Urol. 2010;57:522–8