808677

research-article2018
TAU0010.1177/1756287218808677Therapeutic Advances in UrologyA Benelli, S Mariani

Therapeutic Advances in Urology Original Research

Once-daily 5 mg tadalafil oral treatment for

Ther Adv Urol

2018, Vol. 10(12) 377­–381

patients with chronic prostatitis/chronic DOI: 10.1177/

https://doi.org/10.1177/1756287218808677
https://doi.org/10.1177/1756287218808677
1756287218808677

pelvic pain syndrome

© The Author(s), 2018.
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Andrea Benelli, Simone Mariani, Virginia Varca, Andrea Gregori, Franco Barrese
and Manilo Cappa

Abstract
Background: Chronic prostatitis/chronic pelvic pain syndrome (IIIB CP/CPPS) is a condition of
unclear aetiology. Many approaches have been used without satisfactory results. The aim of
this study is to evaluate the efficacy of once-daily 5 mg tadalafil in pain control and improving
quality of life in patients affected by CP/CPPS.
Methods: Twenty patients affected by chronic prostatitis according EAU (European Association
of Urology) guidelines were evaluated for once-daily 5 mg tadalafil; 14 patients were eligible
for the study. The validated Italian version of the NIH Chronic Prostatitis Symptom Index (NIH-
CPSI) and the International Prostatic Symptom Score (IPSS) questionnaires were submitted to
all the patients. Every patient underwent uroflowmetry and ultrasound prostatic volume at the
beginning and at the end of the study.
Results: All 14 patients eligible for the study reported an improvement of symptoms during
therapy: statistically significant differences were reported in terms of NIH-CPSI (p < 0.000002)
and IPSS (p < 0.0001) during follow-up evaluations. No statistically significant improvement of
uroflowmetry parameters was reported during the treatment.
Conclusions: In our study the daily use of 5 mg tadalafil improves symptoms and quality of life
in patients affected by CP/CPPS after 4 weeks of therapy. A larger population of patients is
needed to confirm the efficacy of this therapy in CP/CPPS.

Keywords: chronic pelvic pain syndrome, chronic prostatitis, tadalafil

Received: 1 August 2018; revised manuscript accepted: 3 October 2018.

Correspondence to:
Introduction anti-inflammatories); according to the literature, Andrea Benelli
Department of Urology,
Chronic prostatitis/chronic pelvic pain syndrome combinations of these therapies appear to ASST-Rhodense, Milan,
(IIIB CP/CPPS) is a chronic condition charac- achieve the greatest improvement.3 A clinical Viale C. forlanini 95,
Garbagnate Milanese,
terized by abdominal, pelvic and perineal pain phenotype system (UPOINT) is used to classify 20024, Italy
frequently associated with obstructive and/or patients with CPPS and to guide therapy; a mul- abenelli@asst-rhodense.it

irritating low urinary tract symptoms. It is also timodal approach seems to be the best approach Simone Mariani
Urology Department,
characterized by the documented absence of uri- for these patients.4 Grimsley and colleagues Madonna delle Grazie
nary tract infection.1 It represents a relatively found that patients with erectile dysfunction Hospital, Velletri, Rome,
Italy
common condition affecting about 8% of men treated with phosphodiesterase 5 inhibitors Virginia Varca
aged 50 years and under.2 Its aetiology is nowa- (PDE5) reported a concomitant improvement in Andrea Gregori
days unclear and the therapeutic approach is still their prostatitis symptoms; their paper advanced Urology Department,
ASST-Rhodense,
a matter of debate. Due to the strong impact on the hypothesis that the relaxation of prostatic Garbagnate, Milan, Italy
patients’ quality of life, many monotherapies duct smooth muscles, increasing wash-out of Franco Barrese
Manilo Cappa
have been proposed in the last decades prostatic reflux products, could significantly Urology Department, Fabia
(antibiotics, alpha-blockers, phytotherapeutics, reduce prostatic inflammation.5 Mater Hospital, Rome, Italy

journals.sagepub.com/home/tau 377

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Therapeutic Advances in Urology 10(12)

Table 1. Patient’s characteristics at enrolment (n = 14).

Mean (median) SD Range

Age (year) 40.14 (39) 8.63 25–50

Prostate volume (ml) 27.5 (26.5) 8.16 16–42

Qmax (ml/s) 19.5 (19.5) 5.03 14–33

PMR (ml) 13.9 (5) 20.30 0–70

NIH-CPSI 27.57 (28) 4.18 21–36

IPSS 4 (4.5) 2.85 0–9

NIH-CPSI, NIH Chronic Prostatitis Symptom Index; PMR, post-micturition residual; SD, standard deviation.

The aim of this study is to evaluate the efficacy of Results

once-daily 5 mg tadalafil therapy in reducing pain From a population of 20 patients with IIIB CP/
and improving quality of life in patients affected CPPS symptoms, 5 patients were excluded for a
by CP/CPPS. positive 4 glasses Meares–Stamey test. Another
patient had to stop taking the once-daily tadalafil
therapy due to muscular pain during the first
Materials and methods week of treatment. Fourteen patients were con-
We evaluated all consecutive patients affected by sidered eligible for the study. Table 1 describes
CP/CPPS treated as outpatients between January the population characteristics and the results of
and June 2016. All the patients included in the the first evaluation (V1). No adverse events were
study gave their informed consent to participate. registered during the treatment. All patients
reported an improvement in symptoms during
Inclusion criteria were the presence of CP/CPPS the therapy: statistically significant differences
symptoms for at least 3 months and negative were reported between the follow-up visits in
Meares–Stamey test. Patients under 18 years old terms of NIH-CPSI (p < 0.000002) and IPSS (p
or over 50 years old with urinary infections or other < 0.0001). The NIH-CPSI and IPSS results at 4,
urological diseases were excluded. All patients 8 and 12 weeks are reported in Tables 2 and 3
treated with antimicrobial drugs during the previ- respectively; Figures 1 and 2 describe the trend of
ous 3 months were excluded. A wash-out period of parameters during the follow-up period. No sta-
at least 2 weeks was requested in patients who tistically significant alterations of uroflowmetry
underwent therapies with alpha-blockers, anti- were reported during the treatment (Table 4,
inflammatory or phytotherapeutic drugs. All eligi- Figure 3).
ble patients during the first evaluation (V1) were
administered the validated Italian version of the
NIH Chronic Prostatitis Symptom Index (NIH- Discussion
CPSI) and the International Prostatic Symptom CP/CPPS is characterized by pelvic or perineal
Score (IPSS). Uroflowmetry and ultrasound pros- pain without evidence of urinary tract infection.
tatic volume were also performed. Follow-up visits Pain is described as arising from several area,
were performed every 4 weeks (V2, V3, V4); every including the perineum, rectum, prostate, penis,
visit included NIH-CPSI and IPSS questionnaires. testicles and abdomen. It is frequently associated
The uroflowmetry parameters were registered only with urinary urgency, frequency, hesitancy and
at 12 weeks (V4). Only patients that completed the weak stream and often with painful ejaculation.6
12 weeks of treatment were considered for the We evaluated the effects of once-daily 5 mg tadala-
study. Therefore, in addition to the descriptive sta- fil for pain relief pain and to improve quality of life
tistic results (mean, standard deviation, range) in patients affected by CP/CPPS. PDE5 inhibitors
one-way analysis of variance (ANOVA) and such as tadalafil work by blocking PDE5-mediated
Student’s t test were used to evaluate the variables hydrolysis of cyclic GMP, leading to increased
NIH-CPSI, IPSS and uroflowmetry. Statistical intracellular GMP levels. Cyclic GMP is a down-
significance was considered if p value was <0.05. stream mediator of nitric oxide (NO), which

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 A Benelli, S Mariani et al.

Table 2. NIH-CPSI during oral treatment with 5 mg daily tadalafil.

NIH-CPSI Visit 1 Visit 2 Visit 3 Visit 4 p*

mean mean mean mean
(±SD; median) (±SD; median) (±SD; median) (±SD; median)

Total score 27.57143 (±4.18; 28) 8.785714 (±3.16; 9) 5.714286 (±3.29; 5) 2.928571 (±2.43; 2.5) <0.000002

Pain score 13.71429 (±3.72; 14) 5.428571 (±2.17; 6) 3.285714 (±1.97; 4) 1.642857 (±1.82; 1) <0.00005

Micturition 5.214286 (±3.80; 5.5) 1.357143 (±1.73; 0) 1.071429 (±1.68; 0) 0.571429 (±0.93; 0) <0.00013
score
Quality of 10.07143 (±5.42; 8.5) 1.928571 (±0.82; 2) 1.285714 (±1.20; 1) 0.7142857 (±1.13; 0) <0.000000033
life score

NIH-CPSI, NIH Chronic Prostatitis Symptom Index; SD, standard deviation.

*ANOVA one-way test.

Table 3. IPSS during oral treatment with 5 mg daily tadalafil.

IPSS Visit 1 Visit 2 Visit 3 Visit 4 p*

Mean 4 (±2.85; 4.5) 1.285714 (±1.20; 1) 0.428571 (±0.51; 0) 0.214286 (±0.42; 0) <0.0001
(± SD; median)

IPSS, International Prostatic Symptom Score; SD, standard deviation.

*ANOVA one-way test.

Figure 1. Symptoms progression.

CPSI, Chronic Prostatitis Symptom Index; QoL, quality of life.

induces smooth muscle relaxation. Nitric oxide colleagues showed how PDE5 inhibitors reverse
synthase, required for NO formation, has been tension in prostatic smooth muscles,10 suggesting
localized biochemically and immunohistochemi- that both NO and PDE5 mediate smooth muscle
cally in the transitional and peripheral zone of the relaxation. Nevertheless, these studies did not
prostate,7 specifically in the nerve fibres and gan- explain how this muscular relaxation could
glia located in the prostatic smooth muscles.8 improve prostatitis symptoms. Kirby and col-
PDE5, the target of PDE5 inhibitors, has been leagues show a retrograde flow of urine into the
localized in the transitional zone.9 Uckert and prostatic ducts of transitional and peripheral zones

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Therapeutic Advances in Urology 10(12)

Figure 2. Uroflowmetry parameters.

PMR, post micturion residual.

Table 4. Qmax (ml/s) and post-micturition residual (PMR) after 12 weeks of oral treatment with 5 mg daily
tadalafil.

Flow 1 (Mean ± SD) Flow 2 (Mean ± SD) p*

Qmax (ml/s) 19.5 ± 5.03 20.14 ± 3.50 <0.698

PMR (ml) 13.92 ± 20.39 15.71 ± 21.38 <0.822

*Student’s t test.

Figure 3. International Prostatic Symptom Score.

in patients affected by prostatitis.11 This study sug- inflammation in a rat model inducing experimental
gested that urinary reflux was the primum movens autoimmune prostatitis (EAP) in the animals.12
for both bacterial and abacterial prostatitis. In a Rats were treated with tadalafil 2 mg/kg or with the
recent study, Okamoto and colleagues investigated EAP vehicle only. The authors showed how the
the effect of tadalafil on pelvic pain and prostatic tactile allodynia was reduced after treatment with

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 A Benelli, S Mariani et al.

tadalafil. They also described a reduction in the management of chronic prostatitis/chronic pelvic
severity of inflammatory lesions in prostatic tissues pain syndrome (CP/CPPS). Urology 2002; 60: 1–4.
after the treatment; this suggests a role played by 2. McNaughton Collins M, Stafford RS, O’Leary
tadalafil in reducing inflammation and pain. MP, et al. How common is prostatitis? A national
survey of physician visits. J Urol 1998; 159:
We hypothesized that the good results in terms of 1224–1228.
pain reduction and improvement in the quality of 3. Anothaisintawee T, Attia J, Nickel JC, et al.
life were due to smooth muscle relaxation in pro- Management of chronic prostatitis/chronic pelvic
static ducts. This could guarantee a greater wash- pain syndrome: a systematic review and network
out of oxidant elements from prostatic tissue, meta-analysis. JAMA 2011; 5: 78–86.
reducing irritant urinary elements and conse-
4. Benelli A, Hossain H, Pilatz A, et al. Prostatitits
quent prostatic inflammation.
and its management. Eur Urol Suppl 2017; 16:
132–137.
This study has some limitations: the small number
of enrolled patients and the lack of a control group. 5. Grimsley SJS, Khan MH and Jones GE.
However, it represents the first paper to confirm Mechanism of phosphodiesterase 5 inhibitor relief
the efficacy of 5 mg daily tadalafil in CP/CPPS. of prostatitis symptoms. Med Hypotheses 2007;
69: 25–26.
Certainly, controlled randomized clinical trials are
need to confirm the results obtained in our study. 6. Litwin MS, McNaughton Collins M, Fowler FJ
Jr, et al. The National Institute of Health Chronic
Prostatitis Symptom Index: development and
Conclusion validation of a new outcome measure. Chronic
Though many drugs have been proposed for IIIB Prostatitis Collaborative Research Network. J
Urol 1999; 2: 369–375.
CP/CPPS, no effective treatment has been
described. In our experience, a daily intake of 7. Burnett AL, Maguire MP, Chamness SL, et al.
5 mg tadalafil guarantees a significant reduction Characterization and localization of nitric oxide
in pain and improvement in quality of life for synthase in the human prostate. Urology 1995; 45:
patients. Although only a small number of patients 435–439.
were enrolled in this study, our results are encour- 8. Takeda M, Tang R, Shapiro E, et al. Effect of
aging and we believe that this therapy should be nitric oxide on human and canine prostates.
given consideration when planning a multimodal Urology 1995; 45: 440–446.
approach. Certainly further studies with larger
populations should be encouraged to achieve 9. Uckert S, Hedlund P, Stief CG, et al.
Histochemical distribution of phosphodiesterase
definitive results.
isoenzymes 3,4 and 5 in the human prostate.
European Urology Supplements 2003; 2(1): 19–19.
Funding
This research received no specific grant from any 10. Uckert S, Kuthe A, Jonas U, et al.
funding agency in the public, commercial or not- Characterization and functional relevance of cyclic
for-profit sectors. nucleotide phosphodiesterase isoenzymes of the
human prostate. J Urol 2011; 166: 2484–2490.
Conflict of interest statement 11. Kirby RS, Lowe D, Bultitude MI, et al.
The authors declare that there is no conflict of Intraprostatic urinary reflux: an aetiological factor
interest. in abacterial prostatitis. Brit J Urol 1982; 54:
729–731.
12. Okamoto K, Kurita M, Yamaguchi H, et al.
Effect of tadalafil on chronic pelvic pain and Visit SAGE journals online
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