Yoshinori Nishino, Department of Urology, Division of Disease Control, Research Field of Medical Sciences, Graduate School of Medicine, Gifu University, Japan. e-mail: email@example.com
To compare the efficacy of two α1-adrenoceptor antagonists, α1A-adrenoceptor-selective tamsulosin hydrochloride and α1D-adrenoceptor-selective naftopidil, in the treatment of lower urinary tract symptoms (LUTS) with benign prostatic hyperplasia (BPH).
PATIENTS AND METHODS
Thirty-four patients (mean age 72.4 years, sd 4.3, range 66–79) with LUTS (International Prostate Symptom Score, IPSS >8) secondary to BPH were enrolled in a randomized crossover study. Seventeen patients were initially prescribed naftopidil 50 mg for 4 weeks, followed by tamsulosin 0.2 mg for 4 weeks (group A); another 17 were initially prescribed tamsulosin 0.2 mg, followed by naftopidil 50 mg (group B). Patients changed to the alternative treatment after a 1-week washout period. Efficacy criteria were improvement in LUTS (IPSS), quality of life (QoL), uroflowmetry, and pressure-flow study (PFS) values based on the treatment with each agent.
At baseline there were no significant differences between the groups in IPSS, QoL, uroflowmetry values or PFS values, except for the volume at maximum desire to void. After treatment with each agent, the IPSS and QoL were significantly improved and the reduction in bladder outlet obstruction confirmed by PFS. Naftopidil was significantly more effective than tamsulosin in relieving nocturia. The increases from baseline (before treatment) to the endpoint (after treatment with each agent) in the volume at first desire and maximum desire to void were significantly higher with naftopidil than with tamsulosin. Involuntary contractions disappeared in two patients with relief of nocturia with naftopidil, but not with tamsulosin. The decrease in other symptoms of the IPSS, QoL, increase in uroflowmetry values and changes in other PFS values were similar for both agents.
The two agents provided similar efficacy in the treatment of LUTS with BPH. However, naftopidil was better than tamsulosin for nocturia. The disappearance of involuntary contraction and the greater increase in first-desire volume with naftopidil may be associated with the relief of nocturia. The α1D-adrenoceptor antagonist is effective in alleviating both voiding and storage symptoms. The α1D-adrenoceptor antagonist may be more effective than the α1A-adrenoceptor antagonist in LUTS with BPH.
Naftopidil is an α1-adrenoceptor antagonist that is used for treating LUTS associated with BPH; naftopidil is assumed to improve urinary flow by relieving urethral pressure, which is elevated by the sympathetic nervous system, because it antagonistically suppresses the noradrenaline-induced contraction of human prostatic urethral smooth muscle . As a result, it is also assumed that naftopidil can alleviate LUTS associated with BPH, like other α1-adrenoceptor antagonists.
Naftopidil and tamsulosin hydrochloride are both now widely used in Japan for treating LUTS associated with BPH . The efficacy of naftopidil has been confirmed in a basic study using rats , and in some clinical studies [4–6]. Whereas tamsulosin has a high affinity for the α1A-adrenoceptor, naftopidil has a high affinity for α1D-adrenoceptor . α1-Adrenoceptors in the urethral smooth muscle are mainly the α1A subtype, and it has been accepted that an α1-adrenoceptor antagonist with a high degree of selectivity for α1A-adrenoceptors is more effective in treating LUTS . However, recent studies showed that α1-adrenoceptors are distributed in the CNS and bladder smooth muscle, and RT-PCR studies show that these are mainly α1D-adrenoceptors, rather than α1A-adrenoceptors [9,10].
When treating LUTS associated with BPH it is necessary to focus not just on symptoms generated by BOO (voiding symptoms), but also on symptoms generated by bladder dysfunction (storage symptoms). Although the mechanism of onset of bladder dysfunction is unclear, relief of storage symptoms, which bother patients with BPH more than voiding symptoms, is very important. Thus, attention has focused on the efficacy of α1-adrenoceptor antagonists with high affinity for α1D-adrenoceptors.
To clarify differences in the treatment of LUTS with BPH between two α1-adrenoceptor antagonists with different α1-adrenoceptor selectivity, we conducted a randomized crossover study and analysed the IPSS, quality of life (QoL), uroflowmetry and pressure-flow study (PFS) values with the two agents.
PATIENTS AND METHODS
This study was conducted at the authors’ institution; informed consent was obtained from all participants before they entered the clinical trial. Thirty-four patients (mean age 72.4 years, sd 4.3, range 66–79; prostate volume 19.8 mL, sd 3.3, range 12.8–28.7) with LUTS secondary to BPH were enrolled in the randomized crossover study (Fig. 1). The patients’ chief complaints were of voiding disturbance and frequent urination; BPH was diagnosed based on symptom scores, a DRE, and TRUS.
Patients with a total IPSS of <7 or a maximum urinary flow rate (Qmax) of >15 mL/s were excluded. Those with neurogenic disorders, UTI, urinary retention, bladder tumour or bladder stones were excluded. No patients had ever received treatment for BPH.
The doses of naftopidil and tamsulosin were determined to be 50 mg and 0.2 mg, respectively, according to the results of each double-blind comparative clinical study [2,5,11]. Moreover, no placebo was used in this clinical trial because naftopidil and tamsulosin were already confirmed to be significantly better than placebo [5,11]. Seventeen patients were initially prescribed naftopidil 50 mg for 4 weeks, followed by tamsulosin 0.2 mg for 4 weeks (group A), and another 17 were initially prescribed tamsulosin 0.2 mg, followed by naftopidil 50 mg (group B). The patients crossed over to the alternative after a 1-week washout period.
Improvement in LUTS and QoL was assessed using the IPSS, uroflowmetry and PFS before treatment (baseline), and after treatment with each agent (endpoint). Voiding symptoms were summed from intermittency, poor flow and straining; and storage symptoms from daytime frequency, urgency and nocturia.
The PFS was conducted using a 6 F double-lumen catheter with constant infusion at a filling rate of 50 mL/min, with rectal pressure monitoring using a 10 F catheter. Involuntary contractions were defined as a rise in bladder pressure of >15 cmH2O. We evaluated the BOO grade using the Schäfer nomogram .
The Wilcoxon rank-sum test for IPSS and QoL, and an unpaired t-test for uroflowmetry and PFS values were used to compare the groups at baseline. A paired t-test was used to assess changes in the IPSS, uroflowmetry and PFS values; all values are expressed as the mean (sd), with statistical significance indicated at <0.05.
Baseline data for the two groups are shown in Table 1; there were no significant differences between the groups in IPSS, QoL or urodynamic values except for the volume at maximum desire to void (MDV). Accordingly, the two agents were evaluated in the same 34 patients (Table 1).
Table 1. The baseline characteristics of the study population, and the changes after treatment with naftopidil and tamsulosin
Naftopidil markedly relieved LUTS; the mean total IPSS decreased significantly from 20.4 (3.5) to 8.9 (3.2), and the individual IPSS and QoL score also decreased significantly. Nineteen patients (56%) had relief of nocturia. Naftopidil significantly increased both the average flow rate (Qave) and Qmax; the postvoid residual volume (PVR) also improved, decreasing significantly. The maximum urethral closure pressure (MUCP) and functional urethral profile length (FUL) decreased, but these changes were minor. Both the volume at first desire to void (FDV) and MDV increased significantly. However, involuntary contraction disappeared in seven patients after the treatment with naftopidil. The results of PFS confirmed that naftopidil decreased the BOO grade in 23 of the 34 patients (67%; Table 2). In addition, detrusor pressure at Qmax (PdetQmax) decreased significantly.
Table 2. The change in the grade of BOO, (I–V) evaluated using the Schäfer nomogram, from baseline to endpoint
Change in BOO grade
Number of patients
IV to III
IV to II
III to II
III to I
IV to IV
III to III
II to II
Tamsulosin similarly relieved LUTS; the mean total IPSS decreased significantly from 20.4 (3.5) to 9.3 (3.0), and the individual IPSS and QoL scores also decreased significantly, with 15 patients (42%) having relief of nocturia. The Qave and Qmax increased significantly, and the PVR decreased significantly. The MUCP and FUL also decreased slightly. Both FDV and MDV increased slightly. The results of PFS confirmed that tamsulosin decreased the BOO grade in 23 patients (67%; Table 2). Involuntary contraction disappeared in five patients after treatment with tamsulosin, and PdetQmax decreased significantly.
The two agents caused no significant difference in voiding symptoms or total IPSS, but relief of storage symptoms was significantly greater with naftopidil (P < 0.01). Of the various storage symptoms, there was a greater relief of nocturia with naftopidil (P < 0.01). There was no significant difference in the QoL score between the agents. Uroflowmetry showed almost no difference in the increase in Qmax and Qave between the two agents. On PFS, the decrease in PdetQmax and FUL were lower with tamsulosin (P < 0.01), but the differences between the agents were only slight. There was no significant difference in MUCP between the agents, and the increases in MDV and FDV with naftopidil were higher than with the other agent (P < 0.05 and 0.01, respectively). Involuntary contraction disappeared in seven patients. In five patients, involuntary contraction disappeared after treatment with both agents. In one patient, involuntary contraction disappeared with naftopidil, but returned when tamsulosin was administered after crossover. In another patient, involuntary contraction did not disappear with tamsulosin but disappeared when naftopidil was administered after crossover. In the two patients in whom involuntary contraction disappeared only when naftopidil was administered, the frequency of urination at night (nocturia) decreased from four to one and FDV increased from 175 to 197 mL, and from 162 to 181 mL, respectively. Nocturia disappeared in four of the seven patients in whom involuntary contraction disappeared. Both agents produced about the same change in BOO grades. There were no adverse events with either agent.
In general, comparative clinical studies with a placebo or another α1-adrenoceptor antagonist are used to confirm the efficacy of α1-adrenoceptor antagonists for treating LUTS associated with BPH. To increase the objectivity and reliability of a study, parallel randomized double-blind controlled studies are used widely, but such studies require many patients, and random allocations are required to avoid study bias. In the case of a small-scale clinical study, the crossover design is common. With this design, the efficacy of an agent is compared in the same patient, not among patients, and thus fewer patients are required and the biases are limited considerably. However, this design is not without problems. Patients may withdraw as a result of improvements or ‘washout’ after the first treatment period, and may not receive the second therapy. Carry-over effects and period effects from one period to the next must also be reduced as much as possible. Furthermore, the crossover design is not suitable for curable conditions .
To confirm the efficacy of naftopidil in the treatment of LUTS associated with BPH, we compared it with tamsulosin; because the study was conducted at one institution (Gifu University) with relatively few patients, the crossover design was adopted. A placebo group is necessary to evaluate the effectiveness of drugs for treating BPH because the effects of the drugs must be compared with those of the placebo, but because the superiority of naftopidil and tamsulosin over placebo was already confirmed [5,11], it was unnecessary to do so again in the present study, as the purpose was to compare the effects of the two agents. Both agents were administered once a day. Because the half-lives of naftopidil and tamsulosin are 10.0–20.1 h  and 9.0–11.6 h , respectively, the effects of these agents are maintained over a long period, but they do not remain in the body for long. We considered that both agents have similar pharmacological properties. To minimize carry-over and period effects, a 1-week washout period was provided between the treatment periods. The efficacy of α1-adrenoceptor antagonists in treating LUTS with BPH is strictly palliative, not curative. Therefore, we considered the crossover design to be valid for comparing the two agents. Furthermore, none of the patients withdrew after the first therapy, and there were no significant differences in patient profiles at baseline. Therefore, we think that it is possible to compare the efficacy of these agents based on the results of the present study.
The doses of naftopidil and tamsulosin chosen were 50 mg and 0.2 mg, respectively, according to the results of clinical trials for patients with BPH in Japan. In a double-blind comparative clinical study of naftopidil, the optimum dose was confirmed to be 50–75 mg , and most Japanese patients with BPH receive a dose of 50 mg. Likewise, although 0.4 mg of tamsulosin is commonly used for treating BPH in Europe or the USA, double-blind comparative clinical studies conducted in Japan [2,11] showed that the optimum dose is 0.2 mg, and this is now the approved dose in Japan.
The efficacy of naftopidil on voiding symptoms was similar to that of tamsulosin; the decrease in the BOO grade evaluated by PFS was also similar between the agents. These decreases supported the efficacy of the two agents on voiding symptoms.
It is generally accepted that because the prostatic urethra primarily includes α1A-adrenoceptors, α1-adrenoceptor antagonists that are selective against α1A-adrenoceptors are more effective, but the present results did not support this hypothesis. Ojima et al. analysed α1-adrenoceptor subtypes in the prostatic urethra of patients with BPH, reporting that 12 men had predominantly α1A-adrenoceptors and 16 mainly α1D-adrenoceptors. Furthermore, they reported that naftopidil was more effective in treating LUTS in the latter patients than the former. In the present study, the α1-adrenoceptor subtypes were not analysed, but because the decrease in BOO and the improvement in voiding symptoms with naftopidil were similar to those with tamsulosin, we think the distribution of subtypes was almost equal. It may therefore be necessary to choose an α1-adrenoceptor antagonist based on the dominant subtype when treating LUTS associated with BPH.
Interestingly, naftopidil was more effective in relieving storage symptoms, particularly nocturia. The increase in FDV and MDV with naftopidil was significantly greater than with tamsulosin. Involuntary contraction disappeared and nocturia decreased from four to one voids per night in two patients only when naftopidil was administered. Chapple and Smith  reviewed the relationship between obstructive detrusor instability and adrenergic neurotransmission in the bladder. They suggested the possibility of using an α1-adrenoceptor antagonist for treating obstructive detrusor instability. Malloy et al. analysed the α1-adrenoceptor subtypes in the human bladder detrusor muscle and reported there are twice as many α1D-adrenoceptors as α1A-adrenoceptors. Hampel et al. investigated the mechanisms of storage symptoms using rats with an obstructed urinary tract, and reported increased bladder weight, more α1-adrenoceptors in the bladder smooth muscle, and a greater α1D-adrenoceptor ratio. Bouchelouch et al. measured isometric tension in the detrusor of patients with BOO and reported a significant increase in contractile force in response to an α1-stimulant (phenylephrine) in patients with BOO than in controls. They also suggested that BOO results in up-regulation of α1D-adrenoceptor in the detrusor of patients with BPH. We think these studies support the effects of naftopidil on storage symptoms observed in the current study. Smith et al., based on an in situ hybridization study, also reported that α1D-adrenoceptors predominate overall in the human spinal cord. In addition, Sugaya et al. injected naftopidil or tamsulosin intrathecally and showed that naftopidil suppressed micturition reflexes significantly more than tamsulosin. Therefore, naftopidil may relieve storage symptoms by affecting the spinal cord as well as the detrusor. Naftopidil may be able to act as a myogenic agent and/or a neurogenic agent for the bladder. Nevertheless, the roles of α1D-adrenoceptors in detrusor overactivity and storage symptoms in patients with BPH have not been fully elucidated.
In recent years it was reported that the prevalence of overactive bladder (OAB) increases with advancing age . Anticholinergic agents are currently used to treat OAB, but elderly men mostly have composite LUTS with both OAB and BOO. Therefore, Ouslander  proposed that men be treated initially with α1-adrenoceptor antagonists, and those not responding or tolerating these agents, and who are not candidates for surgical intervention, may benefit from a trial of an anticholinergic agent, provided they are carefully monitored for the development of urinary retention. Although Athanasopoulos et al. and Maruyama et al. reported that treatment combining an anticholinergic agent with α1-adrenoceptor antagonists is useful for OAB in men with BPH, general consensus has not yet confirmed their clinical effects on BPH with OAB in men. Because we found naftopidil to be more effective than tamsulosin in treating storage symptoms, α1D-adrenoceptor antagonists appear to be useful for treating composite LUTS with BPH and OAB in men.
CONFLICT OF INTEREST
None declared. Source of funding: Gifu University.
This study helps partially to increase our understanding of the relative importance of α1A and α1D adrenoceptor subtypes in the treatment of LUTS. There is now a sufficient volume of clinical data to indicate that naftopidil is clinically effective and thus (even in the absence of a placebo) that the 50 mg dose used in this study is effective. However, there are two explanations of the perceived clinical ‘superiority’ of naftopidil over tamsulosin. The first, favoured by the authors, is the relatively greater α1D selectivity of the former. The latter, favoured by myself, is that the dose of tamsulosin (0.2 mg) is suboptimal, even in the apparently ‘α-blocker-ultra-sensitive’ Japanese population. Nevertheless, the clinical profile of naftopidil remains of potential interest to clinician and patient.