Clinical guidelines for overactive bladder

Transcription

1 International Journal of Urology (2009) 16, doi: /j x Guidelines Clinical guidelines for overactive bladder Osamu Yamaguchi, 1 Osamu Nishizawa, 2 Masayuki Takeda, 3 Osamu Yokoyama, 4 Yukio Homma, 5 Hidehiro Kakizaki, 6 Kenji Obara, 7 Momokazu Gotoh, 8 Yasuhiko Igawa, 2 Naarihito Seki 9 and Masaki Yoshida 10 1 Department of Urology, Fukushima Medical University, Fukushima, 2 Department of Urology, Shinshu University School of Medicine, Matsumoto, Nagano, 3 Department of Urology, University of Yamanashi Interdisciplinary Graduate School of Medicine and Engineering, Chuo, Yamanashi, 4 Department of Urology, University of Fukui Faculty of Medicine, Fukui, 5 Department of Urology, University of Tokyo Faculty of Medicine, Tokyo, 6 Department of Urology, Asahikawa Medical College, Asahikawa, Hokkaido, 7 Department of Urology, Niigata University School of Medicine, Niigata, 8 Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, 9 Department of Urology, Graduate School of Medical Science, Kyushu University, Fukuoka, 10 Department of Urology, Graduate School of medical Science, Kumamoto University, Kumamoto, Japan Preface To date, it has been considered that overactive bladder (OAB) is a unique disease that only specialists can diagnose, with urodynamic studies required for its diagnosis. However, with the definition of OAB in the standard terminology of the International Continence Society (ICS) being extensively amended in 2002, it is now possible to diagnose OAB on the basis of subjective symptoms and without the complexity of urodynamic studies. Moreover, recent epidemiological research shows that patients with OAB are extremely numerous, and in Japan too, it is estimated that among adults aged 40 years or older, the number of OAB patients is approximately 8.1 million. Thus, OAB is by no means a unique disease, but is rather a condition seen in the everyday clinical setting, and it is expected that not only urologists but also general clinicians will increasingly encounter the disease in the future. Therefore, the Neurogenic Bladder Society has prepared this Clinical Guideline for Overactive Bladder. This Guideline is structured into two sections: Basic Information on OAB and Clinical Guideline. Because OAB is a new disease concept, the first half of the basic information provides a detailed explanation of the reasons for the change in definition, the mechanism of onset of OAB for each cause, the epidemiology of the disease, and its effects on quality of life (QOL). The second half of the treatment guidelines deal with symptom-based diagnosis, diagnosis by exclusion, and treatment methods for OAB, and present a treatment algorithm reviewed by each member of the drafting group preparing this guideline. In symptom-based diagnosis, the characteristics of each of the symptoms that constitute OAB syndrome are described in detail: urgency, frequency, and urge urinary incontinence. Among these symptoms, urgency is the essential symptom required for diagnosing OAB. Urgency is a pathological bladder sensation, and questioning by the physician must proceed on the understanding that it is completely different to the strong desire to void that occurs in normal individuals when urination is deferred as much as possible. Furthermore, the important aspect in the new concept of OAB is that the patient is able to be aware of the specific symptoms of OAB such as urgency. Conversely, a diagnosis of OAB is not made if there are no symptoms, even when the bladder undergoes involuntary contraction. For example, OAB could not be the diagnosis in spinal cord injury patients in situations where symptoms cannot be sensed because the bladder sensory Correspondence: Osamu Yamaguchi MD PhD, Department of Urology, Fukushima Medical University, 1 Hikarigaoka, Fukushima-shi , Fukushima, Japan. yamaosa@fmu.ac.jp This is an English translation of text originally published in Japanese in, 2008, Blackwell Publishing Received 9 September 2008; accepted 9 September pathway is completely blocked, even in cases of involuntary contraction of the detrusor muscle. We have ranked treatment methods after reviewing clinical research papers (Medline and Cochrane Library) concerned with the treatment of OAB in the past 10 years (see Table 1). As the history of OAB has only just begun in Japan, randomized controlled trials (RCT) in Japanese patients are limited. Furthermore, many excellent treatment methods are not covered by national health insurance. With an eye to future developments, all clinical research papers were subjected to review, notwithstanding the presence or otherwise of insurance coverage. Since drug therapy is presently at the core of treatment for OAB, each was also ranked with a recommendation grade. Moreover, considering that anticholinergic drugs are the mainstay of effective drug therapy for OAB at present, we have expressly included commentary on the treatment of OAB as a complication of benign prostatic hyperplasia. The algorithm for treating OAB was prepared with general practitioners in mind, rather than specialists. The intent in its preparation was to ensure that initial treatment with anticholinergic drugs can be provided as safely as possible. After a series of investigations, treatment guidelines were proposed for patients with residual urine less than 50 ml and normal urine findings. However, if improvement is not evident, the patient should be promptly referred to a specialist. Hence, we wish to emphasize again that the appropriate treatment for OAB will be realized only with close collaboration between general practitioners and specialists. The completion of this guideline would not have been possible without the dedication of the drafting group members who contributed their valuable time to attend numerous meetings. I wish to express my deep appreciation to the members on the drafting group, and it will be a great pleasure if this guideline contributes to illuminating the respective roles of urological specialists and general practitioners and improving the quality of treatment for OAB. In closing, I wish to note that this guideline edited by the Neurogenic Bladder Society has been endorsed by the Japanese Urological Association, and hereby express my appreciation to the members of the Clinical Guidelines Subcommittee (chaired by Dr. Akihiko Okuyama) for their service. Osamu Yamaguchi Chairman Neurogenic Bladder Society Diagnosis Symptom-based diagnosis Overactive bladder (OAB) is defined as Having urgency, usually with frequency and nocturia, and with or without urge urinary The Japanese Urological Association

2 Guidelines Table 1 Research papers used in preparing this guideline and recommended ranking criteria Ranking of research papers I: The results are evident from a large-scale RCT II: The results are evident from a small-scale RCT III: Has concurrent controls that were not subject to randomization IV: Has historical controls that were not subject to randomization V: Case accumulation research (uncontrolled), with specialist opinions included (RCT: Randomized controlled trial) Ranking of recommendations A: Supported by at least two Level I clinical studies B: Supported by one Level I clinical study C: Supported by Level II clinical studies D: Supported by at least one Level III clinical study E: Only Level IV or V clinical studies are available incontinence. 1 However, other diseases, for example, bladder cancer, cystitis, bladder calculus, and prostate cancer, must be excluded. In other words, OAB is a functional disorder in which urinary urgency is essential, accompanied by symptoms such as frequency, nocturia, and urge urinary incontinence. The diagnosis of OAB is made by confirmation of symptoms and exclusion of other diseases. Urodynamic studies are useful for elucidating the pathological picture of OAB, but are not always necessary for diagnosis or starting treatment. 2 4 As the diseases that should be excluded and the methods of exclusion are described elsewhere, the symptoms will be described below. Symptoms that constitute OAB The symptoms are the most important element for the diagnosis of OAB. The symptoms that constitute OAB are urgency, frequency (daytime and nighttime) and urge urinary incontinence. These symptoms are described as follows by the International Continence Society (Table 2). 1 Evaluation of symptoms Evaluation Variables. The symptoms to be evaluated are frequency, urgency, and urge urinary incontinence. Frequency is evaluated by the number of micturitions. Urgency is evaluated by its frequency (for example, the daily or weekly frequency of occurrence) or degree (for example, the intensity of the sensation or the length of time that the compelling desire to void can be deferred). Urge urinary incontinence is evaluated by its frequency or degree (for example, the volume of leakage) Usually, as frequency, urgency, and urge urinary incontinence are seen as a syndrome in OAB, it is desirable that all these symptoms be evaluated Evaluation Methods. The methods adopted for evaluating symptoms include evaluation via questioning, responses of patients to uniform questionnaires, and records in bladder diaries. Evaluation via questioning is easy, but has inherent problems that include missed questions, leading by the questioner, misapprehension by the respondent, and difficulty of quantification. It is possible to overcome such drawbacks using questionnaires, but as this form of evaluation involves retrospective recall by the respondent, concerns persist about their accuracy. Completion of a bladder diary is a prospective recording survey, and while it is assumed that it may most accurately ascertain symptoms, it Table 2 Symptom Urgency Daytime frequency Nocturia Urge urinary incontinence Symptoms comprising OAB Description lacks practicality. Since there is a concern that reliability decreases with increasing duration of diary recording, the recommended length is from 3 days to about 1 week Symptom questionnaires for OAB A sudden and compelling desire to pass urine that is difficult to defer A complaint by the patient of urinating frequently during the day The complaint of having to wake at night one or more times to void A complaint involving the involuntary leakage of urine either concurrently with or immediately after a sense of urgency Urgency is different from the strong desire to void that occurs in situations when a healthy individual has to refrain from micturition. Urgency is characterized by the sudden occurrence of a compelling desire to urinate. In other words, urgency is a sensation of the bladder that occurs suddenly and when it is sensed, there is no capacity to defer micturition. For descriptive purposes, frequency of micturition is specified as the number of times (for example, at least eight times a day). In OAB, urgency is an essential symptom, but urge urinary incontinence may or not be present. However, the presence or absence of urinary incontinence is a clinically important difference. Therefore, OAB is divided into dry OAB, which does not include urge urinary incontinence, and wet OAB, which does include urge urinary incontinence. Nevertheless, this distinction is not a rigorous one. OAB is a syndrome that is composed of symptoms that include frequency, urgency, and urinary incontinence. Accordingly, rather than evaluating the symptoms individually, it is preferable to make a comprehensive evaluation of multiple symptoms. For the evaluation, questionnaires are easy to use and therefore preferable in the clinical setting. However, there is yet to be an internationally established evaluation method that satisfies these conditions. Research on a questionnaire using Japanese patients with OAB has been undertaken, and the questionnaire shown in Table 3 (Overactive Bladder Symptom Score; OABSS) has been proposed. 19 It is possible that it will be modified via the present investigations, but it is recommended that it be used as a symptom questionnaire for OAB in Japan. Additionally, the OABSS has been used for the evaluation of symptoms in patients diagnosed with OAB. In diagnosing OAB, it is not to be used for differentiating other diseases. It is also not for evaluating diseases other than OAB. As a questionnaire to be used in situations such as screening for OAB in the general population that does not comprise OAB patients, for example, a simplified form of the OABSS (Table 4) is recommended. It is assumed to be used for health surveys, in the general citizenry or those undergoing health checks. Moreover, when using such a questionnaire, it is necessary to pay attention to the fact that these questionnaires have high sensitivity but low specificity for OAB. For example, in the event that only frequency is present as a symptom in Table 4, there are probably many situations where the diagnosis is not OAB The Japanese Urological Association 127

3 O YAMAGUCHI ET AL. Table 3 Overactive Bladder Symptom Score (OABSS) At what frequency have you experienced the following symptoms? Please circle the score that applies best to your condition in the past week. Question Symptom Score Frequency 1 How many times do you typically urinate from waking in the morning until sleeping at night? 2 How many times do you typically wake up to urinate from sleeping at night until waking in the morning? 3 How often do you have a sudden compelling desire to urinate, which is difficult to defer? 4 How often do you leak urine, because you cannot defer the sudden desire to urinate? Sum of scores 0 7 or less or more or more 0 Not at all 1 Less than once a week 2 Once a week or more 3 About once a day times a day 5 5 times a day or more 0 Not at all 1 Less than once a week 2 Once a week or more 3 About once a day times a day 5 5 times a day or more If the question text and options are equivalent, the format does not necessarily have to be that shown above. In this table, the duration is defined as the past week, but depending on the usage, it can be amended to, for example, the past 3 days, or the past month. Whatever the case, it is necessary to specify the duration. Table 4 Screening Questionnaire for Overactive Bladder (SQOAB) Table 5 Main diseases and conditions to be excluded Do you have the following symptoms? I urinate frequently. It is difficult to hold on when I have the sudden compelling desire to urinate. I leak urine because I cannot hold on. People with at least one of the above symptoms may have overactive bladder. Criteria for diagnosis of OAB The recommended diagnostic criteria for OAB are an urgency score for Question 3 of 2 or more, and an OABSS of 3 or more. This is also equivalent to the criteria for OAB in epidemiological surveys 5 and the daily urination frequency of eight times or more, and urgency of once a week or more, which is defined as the lower limit of the symptoms that are regarded as pathological in a supplementary analysis. 20 Also, in the event that the OABSS is used as the standard for assessing the severity of OAB, it is recommended that a total score of 5 or less be defined as mild, a score of 6 11 as moderate, and 12 or more as severe. 19 (Yukio Homma) Diagnosis by exclusion 1. Bladder abnormalities Bladder cancer, bladder calculus, interstitial cystitis (bladder pain syndrome) 2. Pericystic abnormalities Endometriosis, etc. 3. Prostate or urethral abnormalities Prostate cancer, urethral calculus 4. Urogenital infections Bacterial cystitis, prostatitis, urethritis 5. Other Urinary retention, polyuria, psychogenic urinary frequency The main diseases and conditions that should be excluded when diagnosing overactive bladder (OAB) are presented in Table 5. For diagnosis by exclusion, the following should be performed as needed: physical findings, urinalysis, urine cytology, ultrasound examination, cystoscopy, radiography, prostate-specific antigen, and renal function tests. Diseases that should be excluded include those that are life-threatening. Accordingly, if doubts remain about the diagnosis of OAB, or if improvement in symptoms is not seen after starting treatment, it will be necessary to refer the patient to a specialist urologist. Key points of differentiation 1 If urinary occult blood or hematuria is observed, suspect bladder cancer or bladder calculus. 2 The condition characterized by bladder pain on storage of urine, frequency, and urgency is known as interstitial cystitis (painful The Japanese Urological Association

4 Guidelines bladder syndrome). The pathological pictures of overactive bladder and interstitial cystitis appear to overlap in part, but as interstitial cystitis does not respond to normal treatment and requires specialized treatment, refer the patient to a urologist. 3 To exclude prostate cancer, rectal examination and prostate specific antigen tests are recommended. 4 If pyuria is observed, treat first as a urinary tract infection. If pyuria persists, refer the patient to a urologist. 5 In chronic prostatitis, in addition to discomfort or pain in the perineum, groin, and lower abdomen, diverse symptoms such as urinary frequency or discomfort on urination may be presented. At times other than during acute exacerbation, pyuria and bacteriuria are not observed, but expressed prostatic secretion obtained by massaging the prostate and post-massage urine contain leukocytes and bacteria. 6 It is necessary to rule out the presence of urinary retention by palpation or ultrasound examination of the lower abdomen. Psychogenic urinary frequency is characterized by the absence of nocturia. Treatment Behavioral therapy (Hidehiro Kakizaki) Behavioral therapy for OAB can include lifestyle guidance, bladder training, physical therapy, and toileting assistance. Physical therapy includes the methods of pelvic floor exercises and biofeedback therapy. A scientific basis for the efficacy of behavioral therapy has been demonstrated, it is minimally invasive and with no adverse reactions, and combination therapy with other forms of treatment is also possible. Hence, it is one of the modes of therapy that should be considered as the first-line choice for initial treatment of OAB. A uniform consensus on the superiority of combined behavioral therapy and drug therapy over monotherapy is yet to be achieved, but it is the recommended treatment approach in the clinical setting. Nevertheless, several issues remain to be addressed, for the following reasons: long-term results are uncertain; the protocols for specific procedures in each treatment method are yet to be standardized; it is not included in insurance coverage and there is no economic support; and the treatment devices are not approved by the Ministry of Health, Labour and Welfare. Lifestyle guidance There are numerous reports on the relationship between micturition and lifestyle factors, and guidance on precautions to be taken in everyday life for patients with micturition disorder is an important concern for clinicians. Nevertheless, there are few reports on the relationship between changes in lifestyle factors and improvement in micturition symptoms, and the evidence for the therapeutic significance of lifestyle guidance is inadequate. It is possible to anticipate improvement in frequency and urge urinary incontinence in OAB by limiting excessive water intake 21 or caffeine consumption. 22 Also, it is easy to prevent urge urinary incontinence through changes in toilet habits, such as going to the toilet at an early stage, and checking the locations of toilets before going out. In the elderly, useful guidance in everyday life includes establishing an appropriate toilet environment in the house by designing living spaces in close proximity to the toilet and the use of portable toilets or urinals, or skillful clothing modifications. Bladder training Bladder training is a method for increasing bladder capacity through lengthening of the micturition interval, little by little. It is the representative type of behavioral therapy for OAB, and a scientific basis for its efficacy has been demonstrated. Specifically, after explaining the mechanisms of voiding function, and urinary incontinence and continence, a micturition plan is developed, and slowly over min intervals starting from a short length of time, the micturition interval is lengthened, and training proceeds so that finally, a micturition interval of 2 3 h is achieved. As regards the results of bladder training, in urge or mixed urinary incontinence, an improvement rate of 73 90% in evaluations of subjective symptoms, and an improvement rate of 12 16% in evaluations based on bladder diaries have been reported, and randomized studies have shown the superiority of bladder training to no therapy, 23,24 and equivalence to pelvic floor exercises, 25 and drug therapy. 26,27 The mechanism of action of bladder training is not immediately obvious, with various hypotheses suggested: improvement in the inhibitory function of bladder contraction via the cerebral cortex, improvement in the stimulatory function of urethral contraction during bladder filling via the cerebral cortex, central modulation of afferent sensory impulses, and changes in micturition behavior through patient understanding of lower urinary tract function and environmental factors involved in urinary incontinence. 24,25 Physical therapy Pelvic Floor Exercises. The mechanism underlying the efficacy of pelvic floor exercises for OAB is unknown, but it has been shown experimentally and clinically that the detrusor contraction reflex is inhibited by intentional contraction of the pelvic floor muscles. The efficacy of pelvic floor exercises in women with mixed or urge urinary incontinence has been demonstrated in randomized studies, but there is also a report noting that combined therapy with bladder training is appropriate for urge urinary incontinence in women. 31 Furthermore, investigations into the efficacy of pelvic floor exercises for urgency or frequency are inadequate, and there is no evidence in men. Biofeedback Therapy. Biofeedback therapy is a process in which patients are made aware by various means of physiological phenomena that are usually difficult to recognize, and in which this awareness is used in treatment. The foundation of biofeedback therapy for urinary incontinence is pelvic floor exercises, a therapeutic method aimed at greater efficiency of training in which the patient increases their awareness of contractions of the pelvic floor muscles and the degree of contraction. The biofeedback in pelvic floor exercises can be provided via devices such as the vaginal cone, vaginal manometer, or electromyography. Randomized studies of the efficacy of biofeedback therapy have demonstrated its superiority versus no therapy and equivalence to drug therapy, 28,31 but the methods and protocols differ according to the study. Hence, a fixed consensus is yet to be obtained on the comparison between pelvic floor exercises alone and the combination of biofeedback with pelvic floor exercises. 32 Toileting assistance Toileting assistance is an important method of managing micturition in the elderly, but frequently goes unrecognized by caregivers or nurses on the spot, and it is necessary to provide specialist guidance after ascertaining the patient s micturition conditions and environmental factors. Toileting assistance methods for elderly patients with OAB include 2009 The Japanese Urological Association 129

5 O YAMAGUCHI ET AL. timed toileting guidance and patterned toileting guidance. By use of bladder diaries to ascertain the patient s micturition intervals and voiding pattern, the caregiver or nurse can provide toileting guidance to prompt the patient to go to the toilet at fixed times or to match a voiding pattern, before urinary incontinence occurs. The usefulness of this approach has been reported in a small number of randomized studies. 33 (Momokazu Gotoh) For behavioral therapy, 58 research papers were identified, evaluation sheets were prepared for 29 papers, and 13 papers were accepted. Drug therapy Drug therapy forms the basis of treatment for overactive bladder (OAB). There are some reports claiming that the combination of drug therapy plus behavioral therapy is more effective. The drugs for which efficacy and safety have been investigated are the anticholinergic agents, which at present are most commonly used for the treatment of OAB. However, when using anticholinergic drugs, it is necessary to adequately consider adverse reactions due to blockade of the systemic muscarine receptors. The development of new anticholinergic drugs and of drugs with new mechanisms of action is also actively proceeding, and the future promises to see the development of therapeutic drugs for OAB with fewer adverse reactions. In the following, we describe the individual drugs. Anticholinergic drugs Oxybutynin (Recommendation Grade: A). In addition to its antimuscarinic activity, oxybutynin has a direct relaxing effect and paralyzing effect on smooth muscle. It is rapidly absorbed from the gastrointestinal tract, then metabolized in the liver into N-desethyloxybutynin. This metabolite has the same pharmacological effects as oxybutynin itself, and this is believed to be related to its clinical benefits and adverse reactions. In Japan, the usual daily dose is 6 9 mg, in two or three divided doses. Oxybutynin has been extensively evaluated in clinical research, in which its efficacy has been well demonstrated. However, as the incidence of adverse reactions associated with its antimuscarinic activity is higher than that of other anticholinergic drugs, it is recommended that treatment is started from a low dose and titrated gradually to determine the optimal dose. Oxybutynin can pass through the bloodbrain barrier, thereby potentially eliciting central nervous system (CNS)-associated adverse reactions (cognitive impairment, etc.), and caution is especially required in elderly patients. For patients undergoing intermittent catheterization, one method of administration considered to be effective is intravesical infusion (not covered by health insurance), and it is suggested that the adverse reactions are fewer than those with oral administration. Various formulations have been developed to reduce adverse reactions. In Japan, development studies of an adhesive patch formulation are currently in progress, and clinical studies of a sustained-release preparation are also planned. According to the pooled results of 15 randomized controlled studies in which an immediate-release formulation of oxybutynin (the dosage form currently used in Japan) was evaluated in 476 patients with frequency or urinary incontinence, the mean decrease in urinary incontinence was 52% and the mean decrease in the number of micturitions per 24 h was 33%, and the mean subjective improvement rate reported by patients themselves was 74%. However, adverse reactions were reported by a mean 70% of patients. 34 A multicenter open-label study showed that oxybutynin mg significantly improved QOL in OAB patients. 35 As mentioned earlier, oxybutynin can cross the bloodbrain barrier, 36 and has the potential to elicit CNS-related adverse reactions (cognitive impairment, etc.), 37 so adequate caution is especially required in administration to elderly patients. 38 In an investigation in which the effects on electrocardiogram (ECG) findings were monitored in elderly patients with urinary incontinence, no ECG changes were observed. 38 Because of the high incidence of adverse reactions, strategies such as the following are recommended when using oxybutynin: start from a low dose, then if no benefit is seen, titrate the dose gradually to determine the optimal level. 35 As the incidence of adverse reactions is high for immediate-release oxybutynin, a once-daily sustained-release form of oxybutynin has been developed (yet to be approved in Japan). In this formulation, osmotic pressure causes the drug to be released slowly over a 24-h period, which is metabolized slowly in the liver, thereby inhibiting any dramatic changes in the blood concentration of oxybutynin or its metabolite. In a comparative study in which 226 patients with wet OAB received the immediate-release or sustained-release forms of oxybutynin, 39 the number of urinary incontinence episodes per week decreased from 19.8 to 4.4 for the sustained-release form (mean decrease 76%) and from 18.6 to 2.9 for the immediate-release form (mean decrease 83%), showing that there was no difference between the two formulations with respect to efficacy. Of the adverse reactions, the incidences of dry mouth for the sustained-release and immediate-release forms were not significantly different, 47.7% and 59.1% respectively, but significantly fewer patients in the sustained-release group reported severe dry mouth. In a 3-month study comparing sustained-release oxybutynin (10 mg) with immediate-release tolterodine (2 mg, twice daily), the improvement effect of sustained-release oxybutynin on both the number of urinary incontinence episodes and frequency of micturition was superior, and there was no difference between the two preparations with respect to the incidence of dry mouth or other adverse reactions. 40 Intravesical oxybutynin has been used not only for adults but also for children, most frequently in cases of neurogenic detrusor overactivity in which self-catheterization is required. While not a randomized controlled study, the incidence of adverse reactions was lower, bladder capacity was higher, and improvement of clinical symptoms was greater than that reported in oral administration. 41,42 However, adverse reactions were still observed after intravesical infusion, and some patients are averse to continuing treatment because of the complexity of the method of administration. Additionally, oxybutynin is also being developed in other formulations. The incidence of adverse reactions for a suppository form (yet to be approved in Japan) is reported to be lower than that for the conventional oral form. 43 As regards oxybutynin delivered by adhesive patch, a report from the West indicates that improvement in OAB symptoms is equivalent to that obtained with an oral formulation, and that the incidence of the adverse reaction dry mouth is significantly decreased. 44 In a comparative study versus immediate-release tolterodine, there was no difference between the two preparations with respect to improvement in OAB symptoms, but the incidence of dry mouth was significantly lower in the adhesive patch group. However, a relatively high incidence of skin reactions at the site of administration was observed in the adhesive patch group. 45 Propiverine (Recommendation Grade: A). Propiverine is a drug with antimuscarinic activity and calcium antagonist activity. Much remains unknown about its pharmacokinetics and the effects of its metabolites. Overseas clinical studies have shown that propiverine is useful for OAB symptoms, and that adverse reactions are also few. In Japan, propiver The Japanese Urological Association

6 Guidelines ine is most often used to treat frequency and urinary incontinence, and its safety has been assured. The daily dose employed in Japan is 20 mg (in one or two divided doses). Large-scale randomized studies comparing its efficacy and safety at this dose with those of placebo and other drugs have been conducted. According to the pooled results of nine randomized studies in 230 patients with detrusor overactivity, 34 the improvement rate in the frequency of micturition was 30% and the increase in bladder capacity was 77%. In a multicenter study that recruited 113 spinal cord-injury patients with neurogenic detrusor overactivity, 46 bladder function tests showed that propiverine (15 mg, twice daily) increased the maximum bladder capacity by a mean 104 ml, and significantly increased bladder compliance in comparison with a placebo. Meanwhile, residual urine was significantly increased from 50 ml to 87 ml in the propiverine group. Subjective improvement was reported by 63% of patients taking propiverine, a significantly higher figure than that reported by 23% of patients taking a placebo. Among adverse reactions, the incidence of dry mouth was 37% (placebo, 8%) and that of eye accommodation disorder was 28% (placebo, 2%). Furthermore, in a comparative study in which 366 patients with urgency or urge urinary incontinence received propiverine (15 mg, twice daily), oxybutynin (5 mg, twice daily), or placebo, 47 there were no differences between propiverine and oxybutynin for usefulness in bladder function tests, but the incidence and severity of dry mouth were significantly lower in the propiverine group. According to the results of a placebo-controlled study of effects on ECG findings and the efficacy of propiverine (15 mg, twice daily) in 98 patients with urgency, or urge or mixed urinary incontinence, 48 improvement in the propiverine group was significant compared with that in the placebo group, with the daily frequency of micturition improving from 8.7 to 6.5 and the daily frequency of urinary incontinence improving from 0.9 to 0.3. However, there were no significant changes in either group with respect to resting ECG findings or Holter ECG findings. Tolterodine (Recommendation Grade: A). Tolterodine was the firstever drug approved for the treatment of OAB, and is the most widely used drug for this indication in the West. It has no selectivity for muscarinic receptor subtypes, is well distributed to and has a high binding affinity for the bladder, and as compared with the salivary glands, is highly selective for the bladder. These findings have been obtained in both animals and humans. In 4 mg once-daily dosing, tolterodine is a drug for which there is established, wide-ranging evidence for efficacy and safety in OAB patients, including the elderly and patients with severe OAB, improving OAB symptoms as a matter of course, as well as QOL. The incidence of discontinuations and dropouts due to adverse events in a phase III study was comparable to a placebo, 5.3%, the treatment continuation rate in a long-term study was a high 77.1%, and it was confirmed that the incidence of adverse reactions does not increase in long-term administration. Tolterodine has relatively low lipid solubility, implying that transfer to CNS tissue will be low, and the lack of effects of this drug on the CNS has been confirmed in the clinical setting. Given the above, it is considered that tolterodine is a drug for which a high treatment continuation rate can be anticipated in the long term. In a phase III study (conducted as a bridging study in Japan and South Korea) 49 in which 608 patients with wet OAB were assigned to extended-release tolterodine (4 mg, once daily), oxybutynin (3 mg, three times daily), or a placebo, the efficacy of tolterodine was found to be non-inferior to that of oxybutynin. Tolterodine significantly decreased the frequency of urinary incontinence compared with the placebo, with a median reduction of 79% in the frequency of urinary incontinence for tolterodine. Furthermore, compared with the placebo, tolterodine significantly improved the frequency of micturition, volume voided per micturition, and QOL as measured by King s Health Questionnaire (KHQ). The incidence of adverse reactions with oxybutynin was significantly higher than that with placebo or tolterodine, and in particular, the frequency and severity of dry mouth with oxybutynin were significantly higher than those with tolterodine. Additionally, in a long-term study of safety in administration of extended-release tolterodine (4 mg, once daily) for 12 months in 188 Japanese OAB patients who completed this study, 50 there was no tendency for the incidence of adverse events to increase in long-term administration; 145 patients continued treatment for 12 months with a high treatment continuation rate of 77.1%. As regards the effects of extended-release tolterodine on QOL of OAB patients, in a report in which the KHQ and SF-36 were the QOL parameters, 51 tolterodine significantly improved the six domains of the KHQ in comparison with the placebo, but there was no effect on the parameters of the Short Form-36 Health Survey (SF-36). In a comparative study of extended-release tolterodine (2 mg, 4 mg) versus sustained-release oxybutynin (5 mg, 10 mg), 52 tolterodine 4 mg significantly improved bladder condition as a subjective symptom, in comparison with oxybutynin 10 mg, and the frequency of dry mouth was also reported to be significantly lower. The frequency of OAB increases with advancing age, but concern has been expressed regarding the occurrence of adverse reactions to anticholinergic drugs. An investigation into effects in those aged 65 and over and those aged below 65 years 53 showed that extended-release tolterodine was significantly efficacious compared with the placebo in both groups, and there were no differences in benefits or safety between the elderly and non-elderly populations. It is important to identify OAB symptoms that have the greatest effect on QOL and the degree of suffering from them for improving the patient QOL. In the IMPACT trial in OAB patients conducted in a primary care setting, 54,55 the patient perception of bladder condition was evaluated for the symptoms that were most troublesome. After administration of tolterodine, improvement in all OAB symptoms was reported by approximately 80% of patients, and the percentages of patients with improvement in the most troublesome symptoms were 86.3% for urgency, 78.0% for daytime frequency, 78.5% for nocturia, and 74.6% for urge urinary incontinence. 55 Additionally, in a study involving patients with wet OAB, 56 the efficacy of tolterodine over the entire day was investigated in four 6-h time periods. Compared with placebo, tolterodine significantly improved the volume voided per micturition, the frequency of micturition, and the frequency of urinary incontinence in each of the four time periods. As the drug was effective at all time periods within each day, it was concluded that it could address both daytime and nocturnal symptoms. In a study in which the efficacy of extended-release tolterodine was evaluated by severity of urinary incontinence in patients with OAB symptoms for at least 6 months, 57 treatment with tolterodine for 12 weeks improved the frequency of urinary incontinence, the frequency of micturition, and the volume voided per micturition, regardless of the severity of the patient s urinary incontinence (weekly frequency of urinary incontinence before the start of treatment). According to a report comparing a 1-blocker monotherapy (tamsulosin 0.4 mg) with the combination of an a 1-blocker plus immediaterelease tolterodine (2 mg, twice daily) in patients with urodynamic study-proven lower urinary tract obstruction and detrusor overactivity, 58 the findings in the two-drug combination therapy group consisted of significant improvement from baseline in post-treatment QOL (Urolife benign prostatic hyperplasia (BPH) QOL questionnaire), a significant decrease in maximum detrusor pressure, and a significant decrease in maximum involuntary contraction pressure. There were no instances of 2009 The Japanese Urological Association 131

7 O YAMAGUCHI ET AL. acute urinary retention, and for residual urine, no significant increase was observed as a result of coadministration of an anticholinergic drug. Solifenacin (Recommendation Grade: A). Solifenacin is a new anticholinergic drug created and developed in Japan, where it was the first drug to be approved for the treatment of OAB. Solifenacin is relatively highly selective for the muscarinic receptor M 3, and is more highly selective for the bladder than for the salivary glands. The maximum plasma concentration is reached 5 h after administration, the half-life is a relatively long 50 h, and this extremely gradual pharmacokinetic profile may be related to the persistence of efficacy and reduction in adverse reactions. Solifenacin shows excellent benefits for urgency, frequency, and urge urinary incontinence in OAB. In particular, resolution of urinary incontinence is seen in more than 50% of patients with urge urinary incontinence (including the mixed form). Solifenacin is a drug for which the dose can be adjusted, with treatment started at 5 mg once daily and increased to 10 mg, depending on symptoms and effects. The rate of discontinuation of treatment due to adverse events is 6.5% (82/1267 patients), suggesting that solifenacin is a drug that can be taken continuously. The efficacy and safety of solifenacin were investigated in a phase III clinical study conducted in 1593 OAB patients in Japan in which patients were randomized to solifenacin 5 mg and 10 mg, propiverine 20 mg, or placebo for 12 weeks. 59 The study showed that for the change in frequency of micturition at the final evaluation, the primary endpoint, solifenacin was not inferior to propiverine. Compared with the placebo group, the frequency of urgency episodes, frequency of urinary incontinence, and frequency of urge urinary incontinence were significantly decreased, and the volume voided per micturition was significantly increased in the solifenacin 5-mg and 10-mg groups. Furthermore, resolution or urinary incontinence was reported in more than 50% of patients in the solifenacin 5-mg and 10-mg groups. In the QOL evaluation using the KHQ too, the QOL score in the solifenacin group was significantly higher than that in the placebo group. The incidence of adverse reactions in this study was 33.6% in the solifenacin 5-mg group, 52.8% in the 10-mg group, and 42.0% in the propiverine 20-mg group. Furthermore, the incidence of dry mouth, the greatest problem with anticholinergic drugs, was lowest in the solifenacin 5-mg group, 16.7%, versus 34.1% in the solifenacin 10-mg group, and 25.5% in the propiverine 20-mg group. In a long-term administration study conducted in 252 OAB patients in Japan 60 in which treatment was started with solifenacin 5 mg, then increased to 10 mg depending on symptoms and efficacy and continued for 52 weeks (or 60 weeks), solifenacin was shown to have a long-term improvement effect on OAB symptoms. Furthermore, in about 60% of patients, satisfactory and adequate improvement in the symptoms of OAB was obtained at the starting dose of solifenacin 5 mg, and in the remaining 40% or so of patients, symptoms were further improved and satisfactory efficacy was obtained by increasing the dose to 10 mg. This study confirmed that there were no safety concerns, with the adverse reactions remaining within the tolerable range, even at the higher dose. Additionally, a high treatment continuation rate was obtained, with the percentage of patients who continued treatment to the final hospital visit being 81% in the 5-mg group and 75% in the 10-mg group. In Europe, Chappel et al. study compared solifenacin 5 mg (or 10 mg) versus extended-release (ER) tolterodine 4 mg in 1200 OAB patients. 61 This study was planned with the objective of comparing a drug with an adjustable dose versus another drug at a fixed dose. This study, in which the dose could be increased at the patient s request if efficacy was inadequate at the starting dose, can be regarded as a clinical study conducted in the everyday clinical setting. In the solifenacin group, 48% of patients had requested and received a dose increase to 10 mg by week 4 after starting treatment. In the tolterodine ER group by contrast, 51% of patients requested a dose increase, but since the dose could not be increased because of the approval dosage conditions, a placebo was given. For the change in the frequency of micturition at the final evaluation, the primary endpoint, solifenacin was demonstrated to be non-inferior to tolterodine ER. Compared with the results for the tolterodine ER group, urgency, urinary incontinence, and urge urinary incontinence were significantly improved in the solifenacin group, and excellent improvement was obtained, with urinary incontinence resolved in about 60% of patients in the solifenacin group. Most of the adverse events in this study were mild or moderate. The rates of treatment discontinuation due to adverse events were comparable in each group, 3.5% in the solifenacin group versus 3.0% in the tolterodine ER group. Hence, this study demonstrated that solifenacin is a drug for which the dose can be adjusted and for which treatment can be tailored to patient needs. Moreover, by 4 weeks after starting treatment, the frequency of urinary incontinence in the solifenacin 5-mg group was significantly lower than that in the tolterodine ER 4-mg group. 62 In an overseas phase III clinical study (placebo-controlled, doubleblind study), 63 pooled analyses of four overseas phase III studies, an overseas long-term study, 71 and an open-label study in the USA (VOLT study), 72,73 solifenacin improved all symptoms of OAB, as well as QOL, and a pooled analysis stratified by patient characteristics confirmed the efficacy and safety of solifenacin in groups including the elderly, patients with severe disease, patients with urinary incontinence, patients with dry OAB, and patients with nocturia but not nocturnal polyuria. Additionally, in post-marketing surveillance conducted in 4450 patients in Germany, solifenacin was found to have no effect on heart rate or blood pressure. 74 Moreover, in placebo-controlled, doubleblind studies (SUNRISE study 75 and VENUS study 76,77 ) with urgency, the major symptom of OAB, as their primary endpoint, the numbers of episodes of urgency in the solifenacin groups were significantly lower than those in the placebo group. The significance of the SUNRISE study is that it was the first to be conducted with the number of urgency episodes as its primary endpoint. Moreover, the secondary endpoint, patient treatment satisfaction, was also significantly improved. In the VENUS study, patient evaluations of urgency were improved in the solifenacin group, and the warning time (the time required from sensing the urgency to micturition) was significantly lengthened. Imidafenacin. Imidafenacin is a therapeutic agent for OAB that is characterized by improved selectivity for muscarinic receptor subtypes M 3 and M 1. Imidafenacin has higher selectivity for the bladder than the salivary gland, and it appears to inhibit contraction of smooth muscle by acetylcholine and inhibits the release of acetylcholine from cholinergic nerve terminals as a result of its M 3 and M 1 antagonistic actions, respectively. It has no calcium antagonistic action. Imidafenacin was approved in Japan for the indication of OAB in April 2007, at a daily dose of 0.2 mg (in two divided doses). In a double-blind controlled study in which 781 patients with wet OAB were assigned to a placebo, imidafenacin 0.2 mg/day, or propiverine 20 mg/day, imidafenacin and propiverine both significantly improved the weekly frequency of urinary incontinence, and the daily frequency of micturitions, and urgency, as compared with the placebo. As regards efficacy, there was no significant difference between imidafenacin and propiverine. The frequencies of adverse reactions and dry mouth in the imidafenacin group were significantly lower than those in the propiverine group. Moreover, the effect on QT interval in the imidafenacin group was not different to that seen in the placebo group. In a long-term administration study (52 weeks) in 478 patients, urinary incontinence was resolved in approximately 60% of patients. Additionally, the increase over time in the frequency of the adverse The Japanese Urological Association

8 Guidelines reaction dry mouth was slight. In clinical studies, the rate of discontinuation due to adverse reactions was 4.6% (54/1172 patients). (When the above phase III and phase II studies are published, the recommendation grade will be A.) Propantheline Bromide (Recommendation Grade: B). Propantheline is a non-selective anticholinergic drug with no selectivity for muscarinic receptor subtypes. It is yet to be adequately demonstrated in urodynamic studies whether propantheline is effective for detrusor overactivity, but a certain degree of usefulness has been confirmed in clinical research. The usual daily dose of propantheline is mg in 1 4 divided doses, but the optimal dose varies between individuals and high doses are required in some circumstances. In a multicenter double-blind study in 154 patients with detrusor overactivity (neurogenic or idiopathic) who were randomized to placebo, propantheline (45 mg/day in three divided doses) or oxybutynin (15 mg/day in three divided doses), there was no significant difference between propantheline and placebo in their effects on frequency, urgency or urge urinary incontinence. 78 Additionally, a crossover study of oxybutynin and propantheline in 23 women with idiopathic detrusor overactivity showed no difference between the two drugs in their improvement effect on symptoms. 79 Flavoxate (Recommendation Grade: C) The mechanism of action of flavoxate on bladder smooth muscle is yet to be elucidated. This drug has no antimuscarinic activity, but appears to have a moderate calcium antagonistic action, inhibitory effect on phosphodiesterase, and a local relaxant effect on smooth muscle. Flavoxate is relatively widely used in Japan (200 mg, three times daily). It has been observed empirically that there are almost no adverse reactions, but it cannot be claimed that its efficacy has been adequately evaluated. Several open-label or controlled studies in patients with detrusor instability, or frequency, urgency, or urge urinary incontinence have been conducted, but the efficacy of flavoxate was found to vary substantially. 80 At a dose of 600 mg or 800 mg in patients with storage symptoms, there were almost no adverse reactions, and nocturia, urgency, and bladder capacity showed a tendency to improve. By contrast, in a double-blind controlled study in which patients were assigned to either placebo or flavoxate (up to 1200 mg/day), no significant clinical efficacy was seen in the flavoxate group, as compared with the placebo group. 81 In a double-blind crossover study of flavoxate 1200 mg/day and oxybutynin 15 mg/day in 41 women with idiopathic motor or sensory urgency, there was no difference between the two drugs with respect to improvement in voiding function test or subjective symptoms, and the frequency and degree of adverse reactions were lower with flavoxate. 82 Antidepressants (Recommendation Grade: C) Several types of tricyclic antidepressants (imipramine, triptanol, anafranil) are indicated for enuresis or nocturnal enuresis, with imipramine the most commonly used drug in the clinical setting. Imipramine has complex pharmacological actions, which include a relatively weak antimuscarinic action, inhibition of serotonin and noradrenaline reuptake, and antidiuretic activity. However, its mechanism of action against detrusor overactivity is yet to be elucidated. Imipramine appears to be useful for nocturnal enuresis in children, but its usefulness as a therapeutic agent for OAB is yet to be adequately evaluated. One investigation reports efficacy in oral administration at a high dose (150 mg/day) to elderly patients with idiopathic detrusor overactivity, 83 while another notes that coadministration of propantheline and imipramine was efficacious. 84 It has been demonstrated in a controlled study in children with nocturnal enuresis that imipramine is effective in 10% to 70% of patients. 85 It is known that serious effects on the cardiovascular system can arise with imipramine and other tricyclic antidepressants, including orthostatic hypotension and ventricular arrhythmia, and as such adverse reactions are prone to occur in children, caution is required. Resiniferatoxin (Recommendation Grade: C) and capsaicin (Recommendation Grade: C) Resiniferatoxin (RTX) is a neurotoxin extracted from the cactus-like plant named Euphorbia resinifera, and has an action similar to that of capsaicin. 86 Capsaicin and RTX are members of the vanilloid family, and both selectively stimulate the unmyelinated sensory nerves (C-fibers) that transmit sensation for temperature and pain, and due to their desensitizing effects at high concentrations, have the effect of eliminating the response to stimulation for long periods. It has been suggested that activation of sub-mucosal C-fibers in the bladder may be involved in detrusor overactivity following spinal cord injury. 87 Therefore, new treatment approaches have been studied for urinary incontinence in patients with such spinal cord-associated detrusor overactivity, involving the selective blockade of submucosal C-fibers in the bladder via intravesicular administration of capsaicin or RTX to desensitize these C-fibers. However, the efficacy and safety of these approaches are yet to be established. Since first being described by Fowler et al. in 1992, 88 intravesicular capsaicin therapy has been reported to be effective mainly for urinary incontinence in neurogenic detrusor overactivity associated with spinal cord injury or multiple sclerosis. De Seze et al. 89 conducted a doubleblind, randomized controlled study using the vehicle, 30% ethanol, as a placebo, reporting that intravesicular capsaicin significantly inhibited spinal cord-associated detrusor overactivity, and that the acute irritation symptoms associated with treatment in the capsaicin group occurred similarly to those in the placebo group. By contrast, intravesicular RTX, first described by Cruz et al. in 1997, 90 promised to have equivalent efficacy to capsaicin, and was said to have the advantage that the acute irritation symptoms seen in capsaicin therapy would not be present. Later, Silva et al. 91 from the same research group administered intravesicular RTX in 14 patients with neurogenic detrusor overactivity, reporting that urinary incontinence was resolved or improved in nine of 12 patients (75%), among whom efficacy was maintained for at least 1 year in seven patients, and with no acute exacerbation of symptoms after instillation. Similarly, Silva et al. 92 also administered intravesicular RTX in 13 patients with idiopathic detrusor overactivity, finding a significant decrease in the number of episodes of urinary incontinence at 1 and 3 months posttherapy, as well as a significant increase in bladder capacity. Kuo 93 administered intravesicular RTX therapy in 41 patients with non-spinal cord-associated detrusor overactivity (of whom the condition was idiopathic in 13 patients) who showed resistance to anticholinergic drugs, reporting clinical improvement in 21 patients (51.2%) overall, and improvement in five patients (38.5%) in the group with idiopathic detrusor overactivity. Giannantoni et al. 94 conducted a controlled study in which 24 spinal cord injury patients with detrusor overactivity were randomized to intravesicular instillation with either 2-mM capsaicin solution (30% ethanol) or 100-mM RTX solution (physiological saline). In the capsaicin group, no significant clinical efficacy was seen, but in the RTX group, the frequencies of daytime catheterization and urinary inconti The Japanese Urological Association 133

9 O YAMAGUCHI ET AL. nence were significantly decreased at 30 days and 60 days after instillation and bladder capacity was significantly increased. Furthermore, acute irritation symptoms were reported in the capsaicin group but no such adverse reactions were evident in the RTX group, highlighting the superiority of RTX therapy. However, in a separate double-blind controlled study in which 39 spinal cord injury patients with detrusor overactivity were assigned to 1-mM capsaicin solution in a glucidic solute vehicle or 100-nM RTX solution in a 10% ethanol vehicle, 95 there were no significant differences between the two groups, with clinical and urodynamic improvement rates at 30 days after intravesicular instillation of 78% and 83%, respectively, in the capsaicin group versus 80% and 60%, respectively, in the RTX group. In the evaluation performed at 90 days after instillation, the benefit was maintained in two-thirds of patients in both groups in whom the treatment was effective. There were no significant differences between the two groups with respect to the frequency, nature, or duration of adverse reactions. Hence, it is possible that the vehicle used may be an important factor in this treatment regimen. Intravesicular RTX may be valuable for spinal cord-associated detrusor overactivity that does not respond to other conservative treatment approaches, but some aspects remain to be investigated, including the selection of the appropriate indication, the optimal concentration, and the method of administration. There are several reports describing its usefulness for non-neurogenic detrusor overactivity, including the idiopathic form, 93,96 and future investigations are anticipated in idiopathic OAB. Botulinum toxin (Recommendation Grade: C) Botulinum toxin is believed to inhibit bladder contraction by blocking the release of acetylcholine from cholinergic nerves, primarily by causing chemical denervation. Depending on the tissue type, an inhibitory effect on the release of noradrenaline may also be present, and it has also been suggested recently that botulinum toxin has an inhibitory effect on the release of neurotransmitters by acting on afferent nerves. Injection of botulinum toxin into the bladder wall is believed to be a promising therapeutic method for OAB, but its usefulness is yet to be adequately explored. In Japan too, greater understanding of this drug is necessary. Overseas, botulinum toxin is used to treat conditions such as eyelid or facial paralysis, spastic paralysis, wrinkles, hyperhidrosis, and esophageal achalasia. A gel form of the drug has also been developed recently. In the urological field, botulinum toxin was first injected into the external sphincter as a treatment for detrusor-external sphincter dyssynergia in spinal cord injury patients. The urethral closing pressure and voiding pressure decreased, and improvement of subjective symptoms was seen in 70 90% of patients. 97 When used for the bladder, botulinum toxin may be administered in different ways; for example, by injection into about 30 locations in the bladder overall, or by injection into 5 7 locations in the bladder trigone. The use of botulinum toxin has been described in patients with storage disorders associated with neurogenic bladder (spinal cord injury, multiple sclerosis, cerebrovascular disorder, etc.), as well as in patients with idiopathic detrusor overactivity, with improvement in subjective symptoms reported in nearly 70 80% of cases, and no serious adverse reactions. 98 In a randomized controlled study in which spinal cord injury patients with neurogenic detrusor overactivity were assigned to either injection of botulinum toxin into the bladder wall or intravesicular RTX, 99 improvement in the frequency of episodes of urinary incontinence and urodynamic study findings was significantly superior in the botulinum toxin group than the RTX group. Other agents Other Anticholinergic Drugs. Darifenacin is a drug with extremely high selectivity for the M 3 receptor subtype, and has also shown higher selectivity for the bladder than the salivary glands in animal studies. However, concern has been raised about adverse reactions involving the salivary glands and gastrointestinal tract, in which M 3 receptors are numerous. The drug is approved in the West, 100 but development was halted in Japan. Drugs with New Mechanisms of Action (under Investigation). Using these drugs, it is possible that the characteristic adverse reactions of anticholinergic drugs (dry mouth, constipation, and impaired contractility of the detrusor muscle) may be absent. b 3 adrenergic receptor agonists. It has been noted that b-adrenergic receptors are present in bladder smooth muscle, which plays a role in bladder relaxation during the storage phase. b-adrenergic receptors comprise b 1, b 2, and b 3 subtypes, and it has been shown that the latter is involved in relaxation of the human bladder. It has therefore been suggested that drugs with high selectivity for b 3 receptors may be useful for OAB, and drugs such as KUC-7483 and YM178 are in development or undergoing evaluation in clinical studies. Potassium channel openers. The opening of potassium channels in smooth muscle cell membranes induces hyperpolarization of smooth muscle, and intracellular influx of calcium is blocked, and a relaxant effect on smooth muscle is thereby produced. The first-developed potassium channel openers were problematic for use in the clinical setting because of their hypotensive activity. Recently though, the development of drugs with high selectivity for the bladder, which are highly effective for OAB (e.g. ZD 094), has been ongoing. In recent times, attention has begun to focus on the role of bladder urothelium. Various substances are released in certain disease states or with stretching of the bladder, and enhancement of the micturition reflex mediated via receptors present on nerve terminals of the sensory nerves of the bladder has come under consideration as a mechanism underlying the onset of OAB. For that reason, interest has turned to drugs that inhibit afferent bladder nerves as potential therapeutic agents for OAB. The sites of action of the abovementioned capsaicin and RTX are possibly the VR (vanilloid)-1 receptors associated with afferent nerves. Bladder urothelium and smooth muscle produce prostaglandins, and such production is increased by various bladder disorders. Prostaglandins not only induce contraction of bladder smooth muscle, but also increase afferent activity by also acting on bladder sensory nerves, enhancing the micturition reflex. Prostaglandin E receptors are classified into four subtypes, of which the EP-1 receptor is found on bladder sensory nerves (mainly C-fibers). At present, hopes have been raised for EP-1 receptor antagonists as therapeutic agents for OAB. Otherwise, tachykinins, which are released from afferent C-fibers, appear to be associated with involuntary contraction of the bladder, mediated via neurokinin receptors on the spinal cord or the bladder side, and hopes have also been raised for antagonists of these neurokinin receptors as therapeutic agents for OAB. Adenosine triphosphate (ATP) is a type of NANC neurotransmitter, which is released from bladder urothelium when the bladder is stretched or in a pathological state. This is believed to elicit OAB via enhancement of the micturition reflex by stimulating sensory nerves, mediated via P2X3 receptors of afferent C-fibers. ATP receptor inhibitors are therefore also considered to be promising therapeutic agents for OAB. (Masaki Yoshida, Yasuhiko Igawa, Kenji Obara and Narihito Seki) The Japanese Urological Association

10 Guidelines For drug therapy, 368 research papers were identified and evaluation sheets prepared for 182 papers. Of these, 53 papers were accepted, and in preparing this revised digest, four were excluded. Moreover, six new papers on tolterodine were added and the previous five papers were deleted. Nineteen new papers on solifenacin were added and the previous two papers were deleted. Neuromodulation Neuromodulation is a therapeutic method that aims to regulate bladder and urethral function by modulation of nerve function, involving stimulation by various methods of the peripheral nerves that control bladder and urethral function. Behavioral therapy and drug therapy are the standard initial modes of treatment for OAB, but in the West, various forms of neuromodulation are used as a secondary therapy in cases of detrusor overactivity that are resistant to such treatment. Noninvasive forms of neuromodulation include transvaginal, transanal, or percutaneous electrical stimulation or magnetic stimulation, while invasive treatment approaches utilize implantable devices. Electrical stimulation Electrical stimulation involves the application of an electrical stimulus to the pelvic floor using a device that employs a percutaneous, transvaginal, or transanal approach. Traditionally, this method was used to treat stress urinary incontinence, but more recently, reports have emerged of its use for urge urinary incontinence as well. The mechanism of action is not well understood, but it appears that it may involve electrical stimulus-induced inhibition of the pelvic nerves by afferent stimulation of the pudendal nerve and hypogastric nerve and inhibition of bladder contraction by stimulation of the efferent hypogastric nerve. However, the procedure is not generally used in Japan because there are no approved electrical stimulation devices and it is not covered by health insurance. There are various electrical stimulation devices, but consensus is yet to be achieved on such factors as the stimulus conditions and the duration of treatment. As regards the treatment of OAB, some reports indicate that electrical stimulation is more effective than placebo, but comparison is difficult because the protocols vary according to the researchers. Classified as an electrical stimulation method, interference lowfrequency therapy involves stimulation of the pelvic floor by an interference wave (low frequency) produced by a mid-frequency electric current. In Japan, its efficacy has been demonstrated in a randomized study versus a sham treatment for frequency, urgency, and urinary incontinence (stress), 105 and long-term results have been published. 106 There is only one electrical stimulation therapy with an approved stimulation device, which is covered by health insurance in this country. Magnetic stimulation Magnetic stimulation involves inducing contraction of the pelvic floor muscles by nerve excitation, via magnetic stimulation of the pelvic floor, and expectations are held out for similar benefits to those achieved by passive pelvic floor exercises. It is a low-invasive mode of treatment that can be provided with the patient still clothed. The duration of treatment and the protocol details are yet to be standardized, and while there is a report of efficacy in a randomized study of OAB in women, 107 it has not been adequately verified. This method is not covered by health insurance, and therapeutic devices have not gained approval from the Ministry of Health, Labour and Welfare. Implantable-type neuromodulation In addition to the above noninvasive treatments, sacral nerve stimulation using implantable-type stimulation electrodes or stimulation devices has been undertaken for OAB with neurogenic bladder, but also for idiopathic overactive bladder, and reports on efficacy and safety are being accumulated. The mechanism of action of neuromodulation for OAB is unknown, but the conceivable mechanisms include inhibition of bladder contraction by stimulation of the efferent nerves controlling the external urethral sphincter, or inhibition of spinal cord pathways or higher nerve pathways via stimulation of the afferent nerve pathway. In relation to invasive neuromodulation therapy or therapeutic devices, the Ministry of Health, Labour and Welfare is yet to approve this type of therapy, and in Japan it is included in the category of experimental therapy. (Momokazu Gotoh) For electrical and magnetic stimulation therapy, 86 research papers were identified, and evaluation sheets prepared for 44 papers. Of these, seven papers were accepted. Treatment of Overactive Bladder as a Complication of Benign Prostatic Hyperplasia Benign prostatic hyperplasia and OAB symptoms The most common cause of lower urinary tract symptoms in men aged 60 years or older is benign prostatic hyperplasia (BPH), a condition that is frequently associated with detrusor overactivity. 108 Such detrusor overactivity was previously known as unstable bladder, but the latter term has now been abandoned and the condition is known as idiopathic detrusor overactivity. 109 Chronic lower urinary tract obstruction produces a decrease in functional bladder capacity and thickening of the bladder wall, resulting in detrusor overactivity. 110 However, the relationship between this pathological state and OAB symptoms is yet to be completely understood. Between 50% and 75% of elderly male BPH patients with lower urinary tract obstruction have OAB symptoms, but this does not necessarily mean that OAB symptoms will be absent when there is no lower urinary tract obstruction. 111 Also, the presence of OAB symptoms does not necessarily imply that detrusor overactivity will be demonstrated. 112 The reason for this is that various causes, other than lower urinary tract obstruction, can contribute to the occurrence of OAB symptoms. Such causes can include urinary tract infection, stroke, cerebral atrophy, cardiac failure, aging-related decreased nocturnal urine-concentrating ability, and adverse reactions of drug therapy. 113 Efficacy of surgical therapy for OAB symptoms in patients with BPH According to the Guidelines for the Treatment of Benign Prostatic Hyperplasia, the patients for whom surgical therapy is indicated are those with urinary retention or BPH-associated complications (urinary tract infection, calculus, renal dysfunction, etc.), and those with overall severity ranging from moderate to severe. Surgical therapy is the most invasive of the treatment options available, but since it is capable of resolving lower urinary tract obstruction, it is regarded as the most highly effective choice for the improvement of micturition disorder The Japanese Urological Association 135

11 O YAMAGUCHI ET AL. Most BPH patients with OAB symptoms report postoperative symptomatic improvement, but the frequency of OAB symptoms persisting after surgical therapy (transurethral resection of the prostate; TUR-P) is 19%, and while the frequency is even higher in patients aged 80 years or older, 115 not all such patients experience recurrence of obstruction. 116 It is a fact that the incidence of recurrence of symptoms rises with the passage of time, but according to long-term observations after TUR-P, OAB symptoms were seen again in 63% of patients after a mean follow up of 12.6 years. 117 There is no consensus view on the effect of TUR-P on detrusor overactivity, with some reports describing improvement after surgery and others showing no improvement. 115,118,119 Even though surgical therapy elicits early improvement of symptoms, it is not necessarily the case that the mechanism of such improvement is due to clearance of the obstruction, and it is possible that the recurrence of symptoms observed in long-term follow up may be caused by various physical changes attributable to aging, rather than lower urinary tract obstruction. 120 Efficacy of drug therapy for OAB symptoms in BPH patients a 1-Aderenoceptor Antagonists (a 1-Blockers). According to the Guidelines for the Treatment of Benign Prostatic Hyperplasia, a 1-blockers are indicated in patients with overall severity ranging from mild to moderate, and benefits may appear relatively rapidly. 114 In double-blind, placebo-controlled studies, significant improvement in the International Prostate Symptoms Score and the maximum urine flow rate were seen, whereupon a 1-blockers became the first-line drug therapy for BPH. 121 Most BPH patients with lower urinary tract symptoms respond to a 1-blockers, regardless of the presence or otherwise of lower urinary tract obstruction, and together with improvements in the maximum urine flow rate and in symptoms of obstruction, improvement in OAB symptoms is also seen. 122 By contrast, OAB symptoms are improved in patients with no lower urinary tract obstruction on pressure flow studies, despite the lack of significant improvement in the maximum urine flow rate after treatment with a 1-blockers. 123,124 Improvement in OAB symptoms due to a 1-blockers seen in patients without lower urinary tract obstruction is a short-term effect that lasts for about 3 months, and exacerbation of the symptoms with a return to the pre-treatment state is evident in long-term treatment for 15 months or longer. 124 As described above, a 1-blockers are first-line drug therapy for OAB symptoms in BPH patients, but their long-term efficacy in patients without lower urinary tract obstruction is yet to be proven. Anticholinergic Drugs. Because anticholinergic drugs improve the symptoms of OAB including urinary frequency, urgency, and urge urinary incontinence, they are widely used for the treatment of idiopathic detrusor overactivity (detrusor instability). For this indication, oxybutynin, propiverine, tolterodine, solifenacin, and imidafenacin have been approved by the Ministry of Health, Labour and Welfare for use in Japan. However, randomized controlled studies to demonstrate the efficacy and safety of anticholinergic drugs for OAB symptoms associated with BPH are yet to be performed. 125 Despite the fact that anticholinergic drugs may be effective in some BPH patients with OAB symptoms, there is ample risk of causing acute urinary retention or chronic urinary retention. At present, the therapeutic positioning of anticholinergic drugs for men with lower urinary tract symptoms is uncertain, and they are contraindicated in patients with severe lower urinary tract obstruction or urinary retention. Combination Therapy of a 1-Blockers Plus Anticholinergic Drugs. A randomized clinical study comparing the benefits of combination therapy involving an a 1-blocker plus an anticholinergic drug versus a 1-blocker monotherapy in BPH patients has been reported. 126 Tamsulosin (0.4 mg) monotherapy and tamsulosin (0.4 mg) plus immediaterelease tolterodine (2 mg, twice daily) were compared over a 3-month period in 50 BPH patients with mild or moderate lower urinary tract obstruction and detrusor overactivity. Significant improvement in QOL was seen in the combination therapy group, and the maximum pressure of involuntary contraction, bladder capacity at involuntary detrusor contraction, and maximum bladder capacity were all improved significantly in the combination therapy group in comparison with the monotherapy group. Residual urine volume did not change significantly, and there were no cases without urinary retention. 126 In a recent large-scale study (TIMES study) involving 879 men with BPH symptoms and OAB symptoms, 127 those who received combination therapy of sustained-release tolterodine (4 mg, once daily) plus tamsulosin (0.4 mg) had a significantly higher evaluation of treatment benefit, and safety and significant improvement were confirmed for bladder diary evaluations and International Prostate Symptom Score. These results demonstrated that combination therapy of an a 1-blocker plus an anticholinergic drug has the potential to be a useful therapeutic method for BPH patients with OAB symptoms, but in order to draw firm conclusions, it will now be necessary to conduct a larger scale and longer term study. At present, it remains uncertain whether combination therapy of an a 1-blocker plus an anticholinergic drug is superior to a 1-blocker monotherapy in BPH patients with OAB symptoms. Other Drugs. Plant extracts and other products are reportedly effective for BPH, but their mechanisms of action and long-term safety are yet to be determined. Efficacy of other treatment methods for OAB symptoms in BPH patients Behavioral Therapy. Methods such as self-regulation of lifestyle habits (restricting alcohol, caffeine, and water consumption), appropriate medication regimen, and bladder training may be effective, but have not been conclusively demonstrated. Electrical Stimulation and Magnetic Stimulation. Efficacy is uncertain. 128,129 (Masayuki Takeda) Treatment algorithm Overactive bladder (OAB) is a pathological syndrome with various causes that is characterized by symptoms of urgency, frequency, and urge urinary incontinence. Hence, it is imperative for clinicians to make an accurate diagnosis of the causative disease and provide the appropriate treatment. When pursuing a diagnosis of OAB, it is important to exclude other diseases with the same symptoms as those of OAB, and at the same time, it should be noted that some of the causative diseases of OAB should be evaluated at least once by a specialist, in order to provide a more appropriate level of treatment. The former include malignant diseases (bladder cancer, prostate cancer), urinary tract calculus (bladder calculus, urethral calculus), and inflammatory diseases of the lower urinary tract (bacterial cystitis, prostatitis, urethritis, interstitial cystitis), and the latter include OAB caused by lower urinary tract obstruction (benign prostatic hyperplasia) and neurological diseases The Japanese Urological Association

12 Guidelines Urgency plus frequency ± urinary incontinence History of neurological disease (cerebrovascular disorder, spinal cord injury, etc.) *1 Yes No *2 Urinalysis Hematuria only *3 Pyuria *4 No hematuria or pyuria on urinalysis *5 Treat urinary tract infection Measurement of residual urine volume *6 Improved No change Little residual urine Copious residual urine *7 Complete treatment Behavioral therapy or drug therapy using anticholinergic drugs, etc. *8 M1 Improved Poor efficacy Continue treatment Specialist evaluation Fig. 1 Algorithm for the treatment of overactive bladder (OAB). In this section we present a treatment algorithm for use by general practitioners, and explain the cautions required in each step if treatment is progressed (see the treatment algorithm in Fig. 1). *1 Patients with OAB symptoms and a history of, or who currently receive, treatment for overt neurological disease (cerebrovascular disorder, spinal cord injury, etc.) should be referred to a specialist. Diagnosis via urodynamic study is necessary. *2 If there is no history of neurological disease, interview the patient again in detail about their symptoms. Specialist evaluation is necessary if urinary incontinence on abdominal pressure, bladder pain, or severe micturition disorder is present. Once these have been excluded, proceed next to urinalysis. *3 If urinalysis discloses hematuria alone (including urine occult blood), and neither pyuria nor micturition pain is present, bladder cancer or another malignant tumor of the urinary tract may be suspected. Urine cytology is frequently positive, but a negative result on urine cytology is not sufficient to rule out malignant tumor. As bladder cancer is often associated with macroscopic hematuria, evaluation by a specialist is necessary if macroscopic hematuria is seen even once. *4 If hematuria and micturition pain are present with pyuria, it is necessary to differentiate inflammatory diseases of the lower urinary tract (bacterial cystitis, prostatitis, urethritis) and urinary tract calculus (bladder calculus, urethral calculus). In the event of clear-cut acute inflammation of the lower urinary tract, provide antimicrobial treatment. If improvement is not obtained in a relatively short time with antimicrobial treatment, specialist evaluation is necessary The Japanese Urological Association 137

13 O YAMAGUCHI ET AL. Transverse section Residual urine volume (ml) = Long axis Short axis Anteroposterior axis /2 Transverse section Sagittal (longitudinal) section Sagittal (longitudinal) section Short axis Long axis Anteroposterior axis Fig. 2 Ultrasonic measurement of residual urine (Example of transabdominal approach). *5 Concern arises if urine findings are normal in male patients with lower urinary tract obstruction due to benign prostatic hyperplasia (see *8). Also, impaired detrusor contractility may be present in elderly patients of both sexes. However, lower urinary tract obstruction and impaired detrusor contractility are diagnosed by specialist tests, and it is not possible for a general practitioner to diagnose these conditions. In such instances, it is known empirically that the residual urine volume is a marker to some extent, but there is no evidence available at present. Urgency plus frequency urinary incontinence History of neurological disease (cerebrovascular disorder, spinal cord injury, etc.) *1. *6 For residual urine volume, there is no cut-off point for which there is clear-cut evidence. However, one rule of thumb in treatment by a general practitioner is to conclude that significant residual urine is present for volumes of 50 ml or more. Figure 2 shows an ultrasonographic method for measuring residual urine volume. *7 For safe treatment with anticholinergic drugs, patients who complain of voiding symptoms, in addition to having a high residual urine volume (50 ml or more) and OAB symptoms, should be excluded from initial treatment and referred to a specialist. *8 As treatment is progressed in accordance with the algorithm, the treatment guidelines diverge for female patients with normal urine findings and low residual urine volume, and for male patients with normal urine findings and low residual urine volume. However, even if OAB symptoms improve with anticholinergic drug therapy, it is necessary to closely monitor the patient s subsequent clinical course for increased residual urine volume and worsening of voiding symptoms, etc. If there is no improvement obtained with lifestyle guidance, behavioral therapy, and drug therapy, the patient should be referred promptly to a specialist for evaluation. Measurement of residual urine volume is obligatory in the OAB treatment algorithm for general practitioners. However, it would appear that due to pressure of work and other reasons, clinicians may not have time to measure residual urine. Therefore, to provide practical guidelines for drug therapy, primarily involving anticholinergic drugs, the following rules are provided, classified according to age and sex. Practical guidelines for drug therapy for overactive bladder: Rules for treatment with anticholinergic drugs, classified by sex and age OABinwomen Anticholinergic drugs can be administered immediately. However, if voiding symptoms*, as well as OAB symptoms, are present, anticholinergic drugs should be administered with caution: for example, starting from a low dose. Since OAB and impaired detrusor contractility may both be present in elderly women (80 years or older) in particular, patients should be referred to a urological specialist if voiding symptoms* are severe or if residual urine is copious (50 ml or more). OAB in men under 50 years of age For OAB in relatively young men, it is recommended that patients be evaluated by a urological specialist at least once, as there may be an underlying comorbid neurological disease (spinal canal stenosis, etc.) or urological disease (prostatitis, etc.). OAB in men aged 50 years or older Because there is a high probability of OAB as a complication of benign prostatic hyperplasia, give top priority to starting an a 1-blocker if voiding symptoms* are confirmed. If there is no improvement in OAB symptoms, an anticholinergic drug can be coadministered, but as there is not adequate evidence in Japan, the patient should still be referred to a urological specialist. * Voiding symptoms is the collective name given to symptoms characterized by difficulty in voiding urine, and include weak stream (the urine flow is weak), intermittent stream (the urine is The Japanese Urological Association