1636 | The α 1 Adrenoceptor Antagonist Tamsulosin for the Treatment of Voiding Symptoms Im- proves Nocturia and Sleep Quality in Women Sun-Ouck Kim, Hyang Sik Choi, Dongdeuk Kwon Corresponding Author: Sun-Ouck Kim, MD, PhD Department of Urology, Chonnam National University Hospital and Medical School 8, Hak-dong, Dong-ku, Gwangju #501-757, South Korea. Tel: +82 62 220 6705 Fax: +82 62 227 1643 E-mail: seinsena@hanmail.net Received February 2013 Accepted March 2014 Department of Urology, Chonnam National Univer- sity Medical School, Gwangju, South Korea. FEMALE UROLOGY Female Urology Purpose: Nocturia is the main cause of disturbance of sleep maintenance and negatively impacts quality of life (QoL). We assessed the effects of the α1-adrenoceptor antagonist, tam- sulosin, on nocturia and quality of sleep, for the treatment of lower urinary tract symptoms (LUTS) in women with a maximal flow rate (Qmax) less than 15 mL/sec. Materials and Methods: From January 2008 to December 2009, women with LUTS [Qmax ≤ 15 mL/s, International Prostate Symptom Score (IPSS) ≥ 8] and nocturia (void/night ≥ 1) were selected for this study. Two hundred ninety six patients completed voiding diary, a question- naire on the Medical Outcomes Study (MOS) sleep scale and underwent follow-up evaluation after 4 weeks of treatment (tamsulosin, 0.2 mg, once daily). Effectiveness was assessed by analysis of the IPSS, the bother score, the Qmax, and postvoid residual urine (PVR). Results: The mean number of voids per night was 2.66 ± 1.3, and the total IPSS and bother scores were 15.2 ± 8.9 and 3.4 ± 1.2, respectively. Clinical parameters, including the IPSS, the bother score, the Qmax and the PVR, improved significantly from baseline after treatment (P < .05). The change in nocturia was -1.12 (P < .05). Concerning sleep quality, the sleep problem index showed a significant decrease. Among the items on the sleep subscale, sleep disturbance, somnolence, and sleep adequacy were significantly changed (P < .05). Conclusion: The α1-adrenoceptor antagonist tamsulosin significantly improved nocturia and sleep quality as well as LUTS in women with low Qmax. Keywords: adrenergic alpha-1 receptor antagonists; therapeutic use; lower urinary tract symptoms; drug therapy; urination disorders; female; quality of life; treatment outcome. 1637Vol. 11 | No. 03 | May - June2014 |U R O LO G Y J O U R N A L Tamsulosin for the Treatment of Voiding Symptoms in Women | Kim et al INTRODUCTION Nocturia is a common symptom in adult women and has a pronounced impact on sleep, quality of life (QoL) and general health.(1) According to the definition of the International Continence Society, “nocturia” is the complaint that an individual wakes one or more times during the night to void urine.(2) Due to the presumed correla- tion between nocturia and bladder outlet obstruction (BOO), most published studies have tended to focus on nocturia in men(3) even though nocturia is also common in women. (4) A large number of studies have demonstrated that a high proportion of patients with nocturia, estimated from 63% to 75%, complain of nocturia as a troublesome symptom.(4,5) The fragmented and disturbed sleep patterns observed in pa- tients with nocturia can result in daytime sleepiness and can lead to serious health risks.(6) BOO is known to cause irritative and obstructive symptoms. Although BOO in women has traditionally been considered uncommon, recent studies have shown that it is an underdiag- nosed cause of female lower urinary tract symptoms (LUTS). (7) BOO may induce secondary changes in the bladder, such as bladder overactivity, that can result in decreased bladder capacity and storage symptoms, including nocturia. Some re- ports have shown that the real incidence of voiding difficulty in women is between 6.5% and 24%.(8) Use of α-blockers has been reported in women with obstructed urine flow.(9-11) Athanasopoulas and colleagues reported that alfuzosin sig- nificantly improved urodynamic parameters and alleviated bothersome symptoms in women with BOO.(11) Interest has focused on the α1D-adrenoceptor subtype in the bladder as an important target in the treatment of LUTS.(12) Tamsulosin is a potent, specific and selective α1-adrenoceptor antagonist that is known to have greater specificity for α1A and α1D receptors than for α1B (13) and that thus might have a role in the management of both voiding symptoms and storage symptoms in women. However, little research has been conducted on the efficacy of α-blockers in female patients with a low maximal flow rate (Qmax) who are suspected of having functional BOO and nocturia. In the present study, therefore, we aimed to determine the effect of tamsulosin on LUTS and nocturia in women with low Qmax. We also attempted to evaluate the related impact of nocturia on sleep quality. MATERIALS AND METHODS Participants and Study Design In this prospective observational study conducted from Janu- ary 2008 to December 2009, 324 women aged > 20 years who had moderate to severe LUTS [International Prostate Symp- tom Score (IPSS) ≥ 8, Qmax ≤ 15 mL/s at voided volume over 150 mL] and nocturia of at least once per night (IPSS nocturia score of question 7) were included. All patients un- derwent urological evaluation before treatment, including a medical history, physical and neurologic examinations, urine analysis, urine culture and urethrocystoscopy. Participants completed three day voiding diary and a questionnaire on the Medical Outcomes Study (MOS) sleep scale. The effective- ness of tamsulosin (0.2 mg/day) was assessed by analysis of the IPSS, the bother score, the Qmax, and postvoid residual urine (PVR). Data for these parameters were acquired at base- line and after 4 weeks of treatment. All participants provided written informed consent with data collection and the study received approval from the local ethics committee and the in- stitutional review board. The study procedures complied with the guidelines provided by the Declaration of Helsinki. Exclusion Criteria Subjects with confused or depressed mental status; taking medications such as sedatives or tranquilizers that may al- ter or control bladder symptoms; with a history of previous surgery for LUTS; any implication of detrusor dysfunction, detrusor sphincter dyssynergia or neurogenic bladder; with symptomatic urinary tract infection; with uropathologic con- ditions, such as urinary stones and urogenital cancer; with pelvic organ prolapse of higher than stage 2; or with a his- tory of insomnia or a sleep disorder were excluded. We also excluded any patients with iatrogenic, anatomic, or neuro- genic causes of BOO. Patients with nocturnal polyuria from the voiding diary, severe symptoms of stress urinary incon- tinence of Stamey grade 3, patients with restricted mobility, and patients who worked at night were also excluded from this analysis. Patients who had received an α-blocker during the 3 months before enrollment and patients with contraindi- cations to the use of α-adrenergic receptor antagonists were also excluded. Medical Outcome Study Sleep Scale The MOS sleep measure yields a sleep problems index and six scale scores: sleep disturbance (have trouble falling 1638 | asleep, how long to fall asleep, sleep was not quiet, awaken during sleep time, and have trouble falling asleep again), sleep adequacy (get enough sleep to feel rested upon wak- ing in the morning, get the amount of sleep needed), daytime somnolence (drowsy during the day, have trouble staying awake during the day, take naps), snoring, awaken short of breath or with headache, and quantity of sleep.(14) Quantity of sleep is scored as the average number of hours slept per night. The other scales and problems index are scored on a possible range of 0-100, with higher scores indicating more of the concept being measured. Statistical Analysis The statistical package for the social science (SPSS Inc, Chicago, Illinois, USA) version 17.0 was used for statistical analyses. Data were analyzed by Student’s t test. P values < .05 were deemed statistically significant. RESULTS The women’s mean age was 58.3 ± 11.2 years (range, 41- 68 years) and the mean nocturnal frequency during the night was 2.66 ± 1.3. The mean duration of symptoms was 20.3 ± 36.6 months. The incidence of hypertension, diabetes melli- tus, and cardiovascular disease was 27.0%, 18.9%, and 5.4%, respectively. Among the subject 28 women discontinued be- cause of lost to follow-up for personal reason (18) and lack of efficacy (10), the remainder 296 women who completed data were selected as subjects for final analysis. After treatment, there was no reported significant treatment related complica- tions. However, 7 reported mild dizziness or fatigue and 3 reported incontinence without discontinuation of α-blocker therapy. Concerning uroflowmetric parameters, the baseline Qmax and PVR were 13.3 ± 7.8 mL/s and 75.3 ± 23.7 mL, respectively. At 4 weeks after tamsulosin treatment, the IPSS total (P = .03), voiding symptoms (P = .01), storage symptoms (P = .05), the bother score (P = .01), Qmax (P = .001) and PVR (P = .001) showed significant improvement from baseline (Ta- ble 1). The overall mean change in nocturnal frequency after tamsulosin treatment was -1.12 times per night (P = .001). Concerning sleep quality, the sleep problem index (P = .012) showed a significant decrease. On the MOS sleep scale, the subcategories of sleep disturbance (P = .004), somnolence (P = .001), and sleep adequacy (from P = .001) changed signifi- cantly after treatment (Table 2). The subcategories of hours of sleep, shortness of breath, and snoring, however, were not significantly changed after treatment. DISCUSSION LUTS resulting from BOO are commonly associated with detrusor overactivity and storage symptoms. The efficacy of α-blockers for relief of the symptoms of BOO has been well demonstrated; however, less information is available on how this treatment affects the increased nocturia and sleep qual- ity. In the present study, we found that treatment with tam- sulosin resulted in significant improvement of both voiding symptoms and storage symptoms in female patients with low Qmax and significant improvement of Qmax and PVR. Fur- thermore, nocturia was significantly reduced after tamsulosin treatment. Thereby, sleep quality was also improved. Tam- sulosin treatment appears to be effective in female patients with a low Qmax with respect to reducing both storage symp- toms including nocturia and voiding symptoms. Therefore, Female Urology Table 1. Changes in IPSS and uroflowmetry parameters after treatment with tamsulosin. Voiding Baseline 4 Weeks after Treatment P IPSS Total 15.2 ± 8.9 13.6 ± 3.4 .003 Voiding symptoms 9.0 ± 6.2 7.7 ± 3.1 .001 Storage symptoms 6.7 ± 3.9 5.8 ± 0.9 .005 Bother symptom 3.4 ± 1.2 2.9 ± 1.6 .001 Uroflowmetric parameters Maximal flow rate (mL/s) 13.3 ± 7.8 20.4 ± 8.2 .001 Residual urine (mL) 75.3 ± 23.7 54.8 ± 27.5 .001 Key: IPSS, International Prostate Symptom Score. 1639Vol. 11 | No. 03 | May - June2014 |U R O LO G Y J O U R N A L therapy could be an initial treatment option for the patients with LUTS associated with low Qmax who do not have other distinct factors causing BOO. The adrenergic receptors found at the bladder neck are α1- adrenergic receptors, and three subtypes have been identified: α1A, α1B, and α1D (15) The α1-adrenergic blocking agents with subselectivity for α1A and α1D might be the most useful in the management of lower urinary tract dysfunction. Accordingly, it was speculated that the α1D receptor might mediate overac- tive symptoms and LUTS, whereas the α1A receptor subtype would mediate obstructive symptoms.(16) Tamsulosin is a po- tent, specific, and selective α1-adrenoceptor antagonist that is known to have greater specificity for α1A and α1D receptors than for α1B (13) and that thus might have a role in the manage- ment of LUTS in women. Currently, there is little objective evidence to support the ef- ficacy of tamsulosin for the treatment of storage symptoms. Alpha-blocker therapy is an established treatment for BOO related to benign prostatic enlargement in men. The use of α-blockers in women with obstructed urine flow has also been reported.(9-11) Kessler and colleagues examined the ef- fect of terazosin on functional BOO in women and concluded that terazosin had significant symptomatic and urodynamic effects in two-thirds of patients.(10) Athanasopoulos and col- leagues reported that alfuzosin induced significant improve- ment of urodynamic parameters and alleviated the bother- some symptoms of patients with BOO.(11) In the present study, we also observed a significant improvement in uro- flowmetric parameters and subjective symptom scores after tamsulosin treatment in patients with a low urine flow rate. Nocturia is common in women and its prevalence increases with age.(17) Although nocturia is not a life-threatening symp- tom, it is known to have a significant effect on QoL, includ- ing sleep quality. Fragmented and disturbed sleep patterns are observed in patients with nocturia and can result in daytime sleepiness and lead to serious health risks.(4) Middelkoop and colleagues suggested that nocturia is a main factor of disturbance of sleep maintenance in adults aged 50 years or older.(5) Su and colleagues reported that nocturia increases the risk of insomnia by 20.6-fold.(6) In our previous study, we already found that nocturia appeared to be associated with further negative effects on sleep quality, health-related QoL and symptom bother in men.(18) For this reason, it is impor- tant to determine the impact of nocturia on sleep quality and related QoL and how they are correlated. In the present study, we found consistent result with the above-mentioned report showing clear correlation between nocturia and sleep quality. Even though men and women share a common micturition character, the definitions used to describe BOO in men do not apply to women. Diagnosis of BOO in women is still contro- versial; however, obstruction is characterized by a decreased flow rate and a high detrusor pressure, both of which are due to increased bladder outlet resistance. Urodynamic study cur- rently remains the gold standard for assessing the presence of BOO by measurement of Qmax and detrusor pressure at Qmax.(7) During urodynamic study, an obstruction is highly suspected when the study results show a low urine flow rate despite a detrusor contraction of adequate power.(19,20) Blai- vas and Groutz suggested the usefulness of the free flow rate, and they reported that BOO can be diagnosed if the free flow Qmax is ≤ 12 mL/s with normal detrusor power.(21) How- ever, abnormal uroflowmetry has been used as a surrogate Tamsulosin for the Treatment of Voiding Symptoms in Women | Kim et al Table 2. Changes in nocturia and medical outcome study sleep scale after tamsulosin treatment. Voiding Baseline 4 Week after Treatment P No. of nocturia 2.66 ± 1.2 1.54 ± 1.1 .001 Sleep problem index I 40.3 ± 16.7 35.9 ± 15.7 .012 Hours of sleep 6.1 ± 1.8 6.2 ± 1.5 .58 Sleep disturbance 39.7 ± 23.0 34.9 ± 21.5 .004 Somnolence 33.2 ± 25.7 28.7 ± 25.9 .001 Shortness of breath 28.4 ± 57.5 27.3 ± 30.6 .68 Sleep adequacy 46.1 ± 22.1 40.7 ± 23.4 .001 Snoring 40.3 ± 16.7 38.3 ± 18.8 .167 1640 | marker for voiding dysfunction.(22) Some authors have sug- gested that an abnormal flow rate of 15 ≤ mL/s can be used for reliable prediction of patients who are more likely to have voiding disturbance.(23) In the present study, considering the invasiveness of urodynamic study and on the basis of a clini- cal diagnosis of suspected BOO, we included patients with a low Qmax of less than 15 mL/s on free uroflowmetry and a complaint of voiding symptoms on the IPSS. In the present study, we clearly found an effect of tamsulosin on both voiding symptoms and storage symptoms for the pa- tients with female LUTS associated with low Qmax. There- fore, it would be logical to expect that α-blocker therapy in patients with a low maximal flow rate and mixed urinary tract symptoms of voiding and storage symptoms. We suggest that clinicians consider α-blocker treatment as an initial medi- cal treatment of choice for these patients. Clinicians should expect improvement of nocturia and related quality of sleep with α-blocker treatment. This study has a few limitations. This small scale study does not have placebo control group. We could not fully evaluate the exact reason of follow-up loss with personal issues from the study. Thus, considering the low number of female pa- tients with low Qmax, a multicenter, double-blind, placebo- controlled trial would be ideal for further determination of the efficacy and safety of α-blocker treatment in these patients. Nocturia is associated with various conditions and circum- stances. The major causes of nocturia fall into three catego- ries: diurnal polyuria, nocturnal polyuria, and low nocturnal bladder capacity. Nocturia may represent nocturnal frequen- cy from the symptoms of frequent voiding of small volumes, possibly secondary to bladder overactivity and decreased nocturnal bladder capacity, or nocturnal polyuria due to large amounts of urine production during the night that may sug- gest pathology other than from the lower urinary tract.(24) An- other limitation of this study was that we could not evaluate the individual cause of nocturia, neither could we consider the effect of treatment with tamsulosin by the exact cause of nocturia. CONCLUSION The α1-adrenoceptor antagonist tamsulosin significantly im- proved nocturia and sleep quality as well as voiding symp- toms in women with a Qmax of less than 15 mL/s. 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