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.
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 blood-brain 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 7.5–15 mg significantly improved QOL in OAB patients.35 As mentioned earlier, oxybutynin can cross the blood-brain 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, propiverine 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 first-ever 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 years53 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 α1-blocker monotherapy (tamsulosin 0.4 mg) with the combination of an α1-blocker plus immediate-release 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 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 M3, 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 Japan60 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, double-blind study),63 pooled analyses of four overseas phase III studies,64–71 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, double-blind studies (SUNRISE study75 and VENUS study76,77) 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 M3 and M1. 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 M3 and M1 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 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 15–60 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 double-blind, 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 post-therapy, as well as a significant increase in bladder capacity. Kuo93 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 incontinence 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.