At the end of the 1990s and early 2000s, naftopidil was administratively approved for the treatment of BPO and BPH-associated LUTS in Japan, China and South Korea, and several comparative studies were published in various designs. Hayashi and associates compared the therapeutic efficacy of naftopidil and tamsulosin hydrochloride for treating BPH-associated LUTS [Hayashi et al. 2002
]. They performed a crossover study. Eighty-five men without improvement in the QOL index on I-PSS using 50–75 mg/day of naftopidil for 4 weeks or longer subsequently received 0.1–0.2 mg/day of tamsulosin, and 89 showing no improvement in the QOL index using 0.1–0.2 mg/day of tamsulosin for 4 weeks or longer switched to 50–75 mg/day of naftopidil treatment. The I-PSS, maximum flow rate, residual urine volume, and adverse events were assessed at baseline and 8 weeks after switching. In the naftopidil-to-tamsulosin group, domains of urgency, slow stream, and straining significantly improved after 8 weeks of tamsulosin treatment compared with those on naftopidil before switching. In the tamsulosin-to-naftopidil group, domains of feeling of incomplete emptying, intermittency, and nocturia significantly improved 8 weeks after switching to naftopidil. These results suggested that naftopidil possibly has a different effect profile compared with that of tamsulosin.
Another randomized, controlled study comparing tamsulosin and naftopidil by Gotoh and associates concluded that the efficacy and safety of naftopidil are comparable to those of tamsulosin [Gotoh et al. 2005
]. The inclusion criteria were a total I-PSS of at least 8, maximum urinary flow rate of less than 15 ml/s with a voided volume of at least 150 ml, and a prostate volume of at least 20 ml. Their final study group comprised 75 men in the tamsulosin group and 69 in the naftopidil group. Although not significant, prostate volume and the total I-PSS score at baseline tended to be larger/higher in the tamsulosin group than in the naftopidil group (mean 33.6 versus
29.0 ml, p
= 0.060 and 17.1 versus
= 0.088, respectively), and uroflowmetry parameters did not differ between the two groups. Patients in the tamsulosin group received 0.2 mg/day for 12 weeks, and those in the naftopidil group were treated with 25 mg/day for 2 weeks, and thereafter, 50 mg/day for 10 weeks. The I-PSS and uroflowmetry were assessed at baseline and 2, 4, 8, and 12 weeks after treatment. At the final evaluation, the IPSS, maximum flow rate, and residual volume improved in both groups, although the significance for residual volume improvement was borderline in the tamsulosin group. Improvement in these values was similar between the two groups. All of the IPSS domains improved in both groups at the final evaluation with no intergroup difference, and the time course and degree of the improvement in variables were also comparable between the two groups. Adverse effects were reported in nine of 95 (9.5%) men in the tamsulosin group and nine of 90 (10%) in the naftopidil group (p
= 0.94). Interestingly, the profile of adverse events was seemingly different between the two groups. The tamsulosin group reported orthostatic dizziness in four, vertigo in one, severe headedness in two, and diarrhea in one, while the naftopidil group reported orthostatic dizziness in one, unsteady gait in one, numbness of the tongue in four, and abdominal pain in one. Systolic blood pressure significantly decreased in the tamsulosin group, and diastolic blood pressure decreased in both groups.
Ikemoto and colleagues also conducted a randomized, prospective study with a different crossover design [Ikemoto et al. 2003
]. Ninety-six men with BPH, total I-PSS of 8 or higher, and maximum flow rate less than 12 ml/s were randomized to the naftopidil-to-tamsulosin group (n
= 43) or the tamsulosin-to-naftopidil group (n
= 53) (8-week initial to 8-week crossover treatment). Two patients were withdrawn from each group because of adverse effects. The final study group comprised 31 men in the naftopidil-to-tamsulosin group and 34 men in the tamsulosin-to-naftopidil group. At baseline, the total I-PSS did not differ between the two groups (17.0 ± 1.1 and 17.5 ± 1.2, respectively), and prostate volume, QOL index, maximum flow rate, and residual volume were similar between the two groups. In both groups, storage and voiding symptom scores were lower at the crossover point than at baseline, and they were also lower at the end of the study than at the crossover point. However, the difference in voiding score at the end of the study compared with at the crossover point in the tamsulosin-to-naftopidil group was not significant. The results were similar for the QOL index. The maximum flow rate and residual volume significantly improved at the crossover point and remained unchanged 8 weeks after crossover in both groups. The authors also performed subanalyses comparing each I-PSS domain before and after the initiation of naftopidil or tamsulosin. Data suggested that naftopidil was more efficient at improving storage symptoms such as pollakiuria, urgency, and in particular, nocturia. Another study performed around the same time with careful recording of frequency volume using a chart showed that naftopidil reduces nocturnal frequency (from 3.0 ± 0.8 to 2.5 ± 0.8, p
< 0.001) with voided volume increased (from 215.6 ± 91.2 to 247.8 ± 97.9 ml, p
< 0.01) in 32 men with BPH-associated LUTS [Masuda et al. 2004
]. These results also suggested that naftopidil is an interesting agent, which possibly improves BPH-associated storage symptoms.
After approval of naftopidil for the management of benign prostatic hyperplasia: studies on long-term consequences
Studies on long-term outcomes of men with BPH-associated LUTS receiving naftopidil have been limited. Although retrospectively, Kawachi and associates reported the long-term outcomes of naftopidil treatment [Kawachi et al
. 2011]. They randomly selected 131 men with I-PSS of 8 or higher from clinical records; 78 and 53 patients were treated with naftopidil and tamsulosin, respectively. Age, prostate volume, uroflowmetry parameters, I-PSS, and the QOL index were equally distributed between the two groups, and the mean treatment duration was 2.7 years (range 1.5–3.4) in the naftopidil group and 2.5 years (range 0.8–3.2) in the tamsulosin group (p
= 0.3156). The overall 5-year treatment discontinuation rate was 38.1% (50/131), and the reasons for discontinuation did not differ between the two groups. These reasons included inadequate improvement (46.4%), adverse effects (21.4%), improved symptoms (10.6%), and unknown (17.9%). Factors predicting treatment failure were analyzed in 70 men in the naftopidil group. The 5-year failure rate was 54.0%. Men with a history of acute urinary retention had a higher failure rate than those without acute urinary retention (p
= 0.0014). However, in the tamsulosin group, the presence of overactive bladder symptoms was a factor associated with treatment failure. These differences in long-term outcomes also suggest a difference in the effect profile between naftopidil and tamsulosin. Although experimental models could explain the association of the lower urinary tract functions with α1D
-adrenoceptor modulations [Chen et al. 2005
], previous studies failed to give its clinical certification.
After approval of naftopidil for the management of benign prostatic hyperplasia: studies focusing on storage symptoms and quality of life issues
Takahashi and colleagues. examined the treatment efficacy of naftopidil in men with BPH, focusing on overactive bladder symptoms [Takahashi et al. 2006
]. They designed the study with inclusion criteria of urinary urgency at least once a day; total I-PSS of 8 or higher; and presence of any domain of pollakiuria, nocturia, or urgency of 3 or higher. The final study group comprised 81 men after one patient (1.2%) withdrew due to dizziness following the administration of naftopidil. Mean prostate volume was 29.6 ± 12.7 ml. Mean I-PSS and QOL index at baseline were 19.1 ± 6.0 and 4.6 ± 0.9, respectively. Mean maximum flow rate and residual volume were 10.9 ± 4.9 ml/s and 48.3 ± 62.4 ml, respectively. In these patients, 6-week treatment with naftopidil reduced the total I-PSS from 19.1 ± 6.0 to 10.5 ± 6.5 (p
< 0.0001), and the QOL index from 4.6 ± 0.9 to 3.2 ± 1.3 (p
< 0.0001). All of the seven I-PSS domains decreased (p
≤ 0.0001), and in particular, the domain for urgency improved significantly (3.1 ± 1.7 to 1.4 ± 1.6, p
< 0.0001). The results on uroflowmetry were comparable with those in previous reports. Yet, outcomes on the frequency volume chart were of note. Daytime and nocturnal frequency decreased from 9.3 ± 2.2 to 8.0 ± 2.3 (p
< 0.0001) and from 2.7 ± 1.5 to 2.0 ± 1.3 (p
= 0.0009), respectively, and voided volume increased from 174.0 ± 70.6 to 188.6 ± 64.3 ml (p
= 0.0453) with no change in daily urine volume. Moreover, nocturnal frequency decreased in men without nocturnal polyuria (from 2.6 ± 0.9 to 1.9 ± 1.2, p
= 0.0135) as well as in those with nocturnal polyuria (from 3.5 ± 1.4 to 2.5 ± 1.2; p
= 0.0006), suggesting naftopidil may also be effective for BPH-associated storage symptoms.
Oh-oka conducted a study focusing on nocturia [Oh-oka, 2008
]. A total of 122 men with BPH, nocturia of three times or more frequent, and no improvement in nocturia, QOL index, and maximum flow rate after 6 weeks of tamsulosin treatment (0.2 mg/day taken in the morning) were selected. The mean prostate volume was 22.1 cm3
(range 20.2–47.4). About 90% of the patients (107/122) were classified as having nocturia without polyuria showing reduced nocturnal bladder capacity. After a 1-week or longer washout period with placebo, the patients received 75 mg/day of naftopidil after dinner for 6 weeks. After conversion, the frequency of nocturia decreased from 3.1 ± 0.6 (range 3–5) to 1.2 ± 0.8 (range 0–2) (p
< 0.0001) in addition to the decrease in daytime frequency (from 7.5 ± 1.9 to 6.9 ± 1.4, p
= 0.0285). Both storage and voiding I-PSS scores improved (from 5.4 ± 3.0 to 2.0 ± 1.8, p
= 0.0006 and from 7.7 ± 3.5 to 2.7 ± 2.1, p
= 0.0006, respectively). The QOL index improved in all patients (from 4.1 ± 0.8 to 1.5 ± 0.8, p
= 0.0006). Correspondingly, the voided volume increased (from 208.1 ± 81.0 to 237.4 ± 76.4 ml). The maximum and average flow rates also improved significantly. With pressure flow studies, the capacity at the first desire to void increased (from 148.3 ± 81.1 to 176.1 ± 76.9 ml), and the maximal cystometric capacity also increased (from 349.8 ± 122.7 to 381.8 ± 136.5 ml) showing borderline differences. Bladder compliance improved (from 16.8 ± 12.9 to 28.5 ± 17.9 ml/cm H2
= 0.0082). Overall treatment success was observed in 85 of the 122 patients (69.7%). Accordingly, it is suggested that naftopidil is possibly effective in men with BPH who are bothered by storage symptoms represented by frequent nocturia.
Recently, Mizusawa and colleagues prospectively studied patients’ preference/satisfaction with 50 mg/day compared with 75 mg/day of naftopidil, and analyzed differences in their background [Mizusawa et al. 2011
]. Patients reporting unsatisfactory improvement in LUTS with 50 mg/day of naftopidil for 4 weeks based on a question ‘are you satisfied with your current urinary state, yes or no?’ received 75 mg of naftopidil once a day for the next 4 weeks (75 mg group). Those having satisfactory improvement at 50 mg/day continued on the same dose (50 mg group). The final study group consisted of 46 men; 35 and 11 men were included in the 75 mg and 50 mg groups, respectively. At baseline, the score for slow stream alone was higher in the 75 mg group than in the 50 mg group (3.6 ± 1.6 versus
2.1 ± 1.9, p
= 0.013). The 75 mg group showed improvement in the I-PSS and QOL index in a time-dependent and dose-dependent manner (baseline versus
4 weeks after treatment, p
< 0.001 in both; 4 weeks after treatment versus
8 weeks after treatment, p
= 0.019 and p
= 0.003, respectively). In the 50 mg group, the I-PSS and QOL index were reduced 4 weeks after treatment compared with those at baseline (p
= 0.004 and p
< 0.001, respectively); these measures were no different between 4 weeks and 8 weeks after treatment. The difference in QOL index (ΔQOL) during the initial 4 weeks with 50 mg/day treatment in the 75 mg group was smaller than that in the 50 mg group (p
= 0.045). Among the I-PSS domains/items, change in nocturia (Δnocturia) alone was smaller in the 75 mg group than in the 50 mg group (p
= 0.046). With regression coefficient analysis, Δnocturia was correlated with ΔQOL both in the 75 mg and 50 mg groups (r
= 0.437, p
= 0.011 and r = 0.663, p
= 0.036, respectively). Although the authors did not perform urodynamic studies, these results suggested that a high score for slow stream at baseline and unsatisfactory improvement in nocturia with a low dose of naftopidil may be important factors for men with BPH-associated LUTS who prefer and benefit from dose escalation of this agent.
A previous report focused on health-related QOL (HRQOL) in men with BPH-associated LUTS receiving naftopidil. Awa and colleagues prospectively studied 56 men with BPH-associated LUTS [Awa et al. 2008
]. Inclusion/exclusion criteria were similar to those of previous studies, and the dose was 50 mg/day. The authors referred to I-PSS and King’s Health Questionnaire (KHQ). KHQ comprises nine domains and 21 questions and was used to assess LUTS [Kelleher et al. 2002
]. Each I-PSS domain improved significantly after 12 weeks of treatment. KHQ scores in all nine domains decreased after treatment, and domains for incontinence impact, role limitations, physical limitations, personal relationships, emotions, sleep and energy, and severity measures significantly improved. Interestingly, patients with overactive bladder symptoms showed significant improvement in all domains except for general health perceptions, while those free from overactive bladder had no improvement in any of the KHQ domains. These results also support the usefulness of naftopidil for treating men with BPH and storage symptoms, leading to improvement in QOL.
Komiya and colleagues performed a study on HRQOL in 99 men with BPH-associated LUTS receiving naftopidil [Komiya et al. 2010
]. They assessed QOL using Short Form-8 (SF-8), an internationally validated questionnaire for HRQOL, consisting of eight domains: physical function (PF), role physical (RP), role emotional (RE), bodily pain (BP), general health (GH), vitality (VT), social function (SF), and mental health (MH) [Tokuda et al. 2009
]. In their study, the dose of naftopidil ranged between 25 and 75 mg/day (96.9% received 50 mg/day or 75 mg/day). At baseline, the I-PSS and QOL index were correlated with each of the SF-8 domains (except for BP). The score for feeling of incomplete emptying was correlated with SF-8 RE, and the score for pollakiuria was correlated with SF-8 SF and RE. The score for urgency was correlated with SF-8 RP and SF, and other I-PSS scores also showed correlations with several SF-8 domains. Eight weeks after treatment, 71% of the patients continued treatment, 17.2% discontinued, and 11.1% were lost to follow up. SF-8 GH improved significantly at 4 weeks and further improved 8 weeks after treatment (47.5 versus
49.5 and 50.6). SF-8 VT also improved 8 weeks after treatment compared with that at baseline (from 50.3 to 51.6). The authors also showed that some domains in the participants impaired at baseline compared with those in the general population recovered to general levels after naftopidil treatment. These results suggest that naftopidil possibly retrieves QOL impaired by BPH-associated LUTS.
Takeda and colleagues examined the efficacy and safety of naftopidil for treatment of neurogenic lower urinary tract dysfunctions [Takeda et al. 2011
]. They prospectively studied 82 patients (40 men and 42 women) with neurogenic lower urinary tract dysfunction. After the stepwise administration of naftopidil for 10 weeks, pressure at maximum urinary flow rate decreased in men (p
< 0.05), whereas it did not in women. Maximum flow rate increased in men (p
< 0.05), but did not in women. Residual urine volume decreased both in men (p
< 0.01) and women (p
< 0.05), and the I-PSS decreased both in men and women (p
< 0.01 in both). Thus, naftopidil has a significant effect on LUTS and some urodynamic parameters in both men and women with neurogenic lower urinary tract dysfunctions.
Ishizaka and colleagues studied the effect of naftopidil on the recovery of lower urinary tract functions after radical prostatectomy in men with localized prostate cancer [Ishizaka et al. 2009
]. Although patients showed significant improvement in symptoms and uroflowmetry parameters, the efficacy of naftopidil was equivocal due to the short observation period (5 weeks) and absence of a control group. The utility of α1
-adrenoceptor antagonists in the management of lower urinary tract disorder following focal therapy for localized prostate cancer is expected to attract greater interest with widespread minimally invasive surgery and brachytherapy [Tsumura et al. 2011
]. Further studies on the role played by α1
-adrenoceptor antagonists including naftopidil are warranted.
It is also known that α1
-adrenoceptor antagonists are associated with ejaculatory dysfunction, and the mechanism of action and the relevance of α1
-adrenoceptor subtypes are of interest in physiological and clinical practice. Masumori and colleagues studied the profile of ejaculatory disorders during BPH treatment with tamsulosin or naftopidil [Masumori et al. 2009
]. They prospectively studied 95 men with BPO or BPH-associated LUTS. These men were randomized to naftopidil (n
= 48) or tamsulosin (n
= 47) therapy. Although the I-PSS and QOL index at baseline were lower in the naftopidil group than in the tamsulosin group (14.8 versus
= 0.049 and 4.3 versus
= 0.005, respectively), age, prostate volume, the maximum flow rate, and residual volume were similar between the two groups. Ejaculatory disorders could be evaluated in 45 men in the naftopidil group and 46 men in the tamsulosin group, and five (11.1%) and six (13.0%) men reported adverse events including ejaculatory disorders, respectively (p
= 0.999). After excluding those who discontinued treatment due to circulatory adverse events, 27 of 40 (67.5%) in the naftopidil group and 24 of 37 (64.9%) in the tamsulosin group reported their sexual activity. Neither naftopidil nor tamsulosin treatment had any influence on the International Index of Erectile Function-5 (IIEF-5) score. Among assessable patients, two of 27 (7.4%) in the naftopidil group and four of 24 (16.7%) in the tamsulosin group reported abnormal feelings on ejaculation, although the difference was not significant (p
= 0.402). The proportion of those who reported a reduction of the semen amount was higher in the tamsulosin group (26.9% versus
= 0.0496). Although further studies are required, naftopidil may possibly be associated with less frequent ejaculatory disorders.
Intraoperative floppy iris syndrome (IFIS), although rare, is problematic in cataract surgery, presenting with progressive intraoperative pupil constriction. Its overall incidence in cataract surgery is 2%, whereas it was reported to be encountered in 63% of men with BPH receiving the α1A
-adrenoceptor antagonist tamsulosin [Chang and Campbell, 2005
]. Oshika and colleagues reported the prevalence of IFIS and the association between α1
antagonists and IFIS in men undergoing cataract surgery [Oshika et al. 2007
]. Of 1015 eyes of 762 men, IFIS was observed in 29 eyes of 25 men (overall incidence 1.1%), and all of them were receiving α1
antagonists. The authors also studied a cohort comprising 110 men (134 eyes) treated with α1
antagonists. Twenty-five of 58 eyes (43.1%) of 50 men receiving tamsulosin developed IFIS, while four of 21 (19.0%) eyes of 19 patients taking naftopidil had IFIS (p
= 0.042). Although it is unclear whether the difference depends on the selectivity of these two agents for α1
-adrenoceptor subtypes, naftopidil might be associated with less frequent IFIS.