Hann-Chorng Kuo M.D., Department of Urology, Buddhist Tzu Chi General Hospital, No. 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan. Email: email@example.com
Botulinum toxin has been recently accepted as a novel treatment for lower urinary tract dysfunctions refractory to conventional treatment. Review of the clinical trials in recent years, botulinum toxin type A has been widely used in the urethra or urinary bladder to treat voiding dysfunction due to detrusor sphincter dyssynergia, incontinence due to neurogenic or idiopathic detrusor overactivity, sensory disorders such as bladder hypersensitivity, overactive bladder, and interstitial cystitis/painful bladder syndrome. Intravesical botulinum toxin type A injection is effective in treatment of urinary incontinence due to detrusor overactivity in men and women, as well as in children. Currently botulinum toxin type A has also been applied to treat lower urinary tract symptoms due to benign prostatic hyperplasia in patients not suitable for surgery. This article reviewed the recent advances of botulinum toxin type A on lower urinary tract dysfunction.
BoNT is one of the most potent natural toxins known. Acute BoNT poisoning causes generalized paralysis and respiratory failure, which takes 3–6 months to recover from after resprouting of the affected nerves.1 BoNT is a protein with a 50-kd light chain and a 100-kd heavy chain. BoNT recognizes and enters neurons by binding to the synaptic vesicle protein, SV2, during neurotransmitter exocytosis when more active receptors are exposed.2 Through endocytosis of this toxin, the disulphide bond is cleaved. The light chain is the true active moiety of the molecule and can combine with SNAP-25 protein to inhibit exocytosis of the neurotransmitter from the vesicles. The affected neuromuscular junctions become paralyzed after injection of BoNT.3 Seven serotypes of BoNT have been identified; types A and B have been most widely used for medical purposes.4 Type B BoNT has been shown to be effective in treating patients with cervical dystonia that is refractory to repeated BoNT-A injections.5
The application of BoNT-A for the treatment of LUTD was initiated the late 1980s. Dykstra et al. described injections of BoNT-A into the external urethral sphincter in spinal cord injury patients to induce chemical sphincterotomy and treat DSD.6 Schurch also reported successful results of urethral BoNT-A injections for treatment of DSD.7 In the past few years, Schurch et al. have reported successful the treatment of SCI patients with neurogenic DO using detrusor BoNT-A injections at multiple sites.8 Later on, intravesical BoNT-A injections were successfully applied to patients with idiopathic DO or overactive bladder.9,10 Furthermore, Maria et al. first published the therapeutic effects of BoNT-A in patients with BPH.11 Because the mechanisms of action of BoNT involve anti-inflammation, therefore, BoNT has currently been tried to treat IC/BPS refractory to medical treatment.12 As the uses of BoNT-A continue to expand in the field of urology, it is important to understand the mechanisms and clinical effects by which the toxin works on different tissue types and disease entities.
There are three commercially available BoNT worldwide. Botox (onabotulinumtoxinA; Allergan, Irvine, CA, USA) and Dysport (abobotulinumtoxinA; Ipsen, Berkshire, UK) is BoNT-A, and Myobloc (Elan Pharmaceuticals, Inc., Princeton, NJ, USA) is BoNT-B. The potency of each toxin is expressed in units of activity. Although there are similarities among the commercial preparations of BoNT, they have different doses, efficacy and safety profiles, and should not be considered generic equivalents comparable by single dose ratios.13 Although the use of BoNT-A in the treatment of LUTD has recently expanded, most of the clinical applications are off-licence, except for NDO. A systemic review has shown a high-level evidence of the use of onabotulinumtoxinA and abobotulinumtoxinA in adults with NDO, but only for abobotulinumtoxinA in children with NDO. Only onabotulinumtoxinA has level 1 evidence supporting its use in IDO, BOO, DSD and IC/PBS.14
BoNT-A injections in treatment of voiding dysfunction
Although urethral BoNT-A injections were first applied in the treatment of voiding dysfunction as a result of DSD, very little has been added to the literature on the use of BoNT-A injections for neurogenic or non-neurogenic voiding dysfunction in the past 5 years. Because urethral sphincter BoNT-A injections potentially have a side-effect of increased urinary incontinence, urethral BoNT-A injection is seldom reported to be a standard procedure in the treatment of voiding dysfunction.
Patients with voiding dysfunction as a result of SCI, pseudodyssynergia or non-relaxing urethral sphincter can be treated with 50–100 U urethral BoNT-A injection.15 Urethral BoNT-A injections can be carried out in the operation room under light intravenous general anesthesia (in men) or at an outpatient clinic without anesthesia (in women). The dose of BoNT-A can be 50 U for patients with detrusor underactivity who wish to void by abdominal pressure after treatment,16 or 100 U for patients with DSD, dysfunctional voiding or poor relaxation of the urethral sphincter.15 Patients are placed in the lithotomy position, after sterilization and draping, BoNT-A solution is injected directly into the urethral sphincter under cystoscopic guidance in men and periurethrally in women. Usually four to eight injections at equal volume of BoNT-A solution is adequate (Fig. 1a). The injection needle should not be inserted too deep to avoid injecting BoNT-A outside the sphincter muscle. With direct visualization of the tight sphincter, the needle is injected at a depth of 0.5 cm at four to eight sites in men. The injection needle should be inserted transcutaneously around the female urethral lumen, and in a longitudinal direction with the lumen to the depth of 1.5 cm at four to eight sites. More injection sites will ensure the percentage of leaking BoNT-A is kept to a minimum and to obtain the maximum drug effect on the urethral striated muscles.
BoNT-A has been used safely in the treatment of several types of neurogenic spasticity, including patients with SCI and DSD.6,7,15 Phelan et al. found that after BoNT-A injection, 67% of patients were able to void smoothly, with postvoid residual decreased by 71% and voiding pressure decreased by 38%.17 In patients with dysfunctional voiding as a result of urethral sphincter overactivity,18 urethral sphincter pseudodyssynergia in patients with cerebrovascular accidents or intracranial lesions,19 non-relaxing urethra as a result of radical hysterectomy,20 and detrusor underactivity, BoNT-A has been shown to have a therapeutic effect in improving voiding efficiency and recovering detrusor contractility in a number of patients with few reported adverse effects.21
In a large series of patients (n = 103) with voiding dysfunction, 40 (39%) patients had an excellent result, 47 (46%) had significant improvement and 16 (15%) had treatment failure. The overall success rate was 84.5% (range 75–100%). Among the 45 patients with urinary retention, the indwelling catheters could be removed or CIC was discontinued in 39 (87%; Table 1).15
Table 1. Therapeutic effects of urethral sphincter BoNT-A injections of different voiding dysfunction
Non-relaxing urethral sphincter
Cauda equine lesion
Idiopathic detrusor underactivity
The actual pathophysiology of non-neurogenic voiding dysfunction has not been completely understood. The bladder neck, the prostatic smooth muscle as well as the urethral sphincter might play a role. Lim injected 100 U of BoNT-A transurethrally into the bladder neck and proximal prostatic urethra laterally at 10 sites, and found 87.5% of patients had a >50% reduction of IPSS from baseline.22 Similarly, Chen et al. also reported bladder neck and urethral BoNT-A injections improved LUTS, and increased maximum flow rate in men with refractory LUTS and a small prostate.23 It is necessary to carry out clinical trials to clearly define the role of BoNT-A on urethral sphincter dysfunction and verify which voiding dysfunction can really benefit from urethral sphincter BoNT-A injections.24
BoNT-A injections for overactive bladder
OAB is a symptom syndrome characterized by urgency frequency with or without urge incontinence that might affect the patients' QoL.25 Recent investigations have shown the urothelial release of neurotransmitters, such as acetylcholine, adenosine triphosphate and neuropeptides substance P, and the expression of transient receptor potential vanilloid receptor subfamily-1 and purinergic receptors P2X3 strongly imply a role for the urothelium in human bladder mechanosensation.26–28 The urothelial release of ACh and ATP on bladder filling has been found to increase with aging29 and in spinal cord NDO,30 suggesting an abnormal release of these neurotransmitters in the pathophysiology of DO. In treatment of IDO with intradetrusor injection of BoNT-A, a decreased immunoreactivity of P2X3 expression in suburothelial fibers has been noted, which correlates with an improvement in patients' sensation of urgency.31 A recent study also showed detrusor wall BoNT-A injections can modulate the expression of nerve growth factor and TRPV1 on the urothelium in bladder outlet obstruction in rats.32 Established drug therapies also showed that the effect of BoNT-A on OAB might act partly through afferent mechanism.33
Intravesical BoNT-A injection has been well documented to be effective in treating adult patients with OAB and IDO refractory to antimuscarinic therapy.9,10,34–40 The bladder capacity increases, intravesical pressure decreases and incontinence episodes reduce after intravesical BoNT-A injection.9 The pooled random effects estimate of effect across three randomized placebo controlled studies showed that with BoNT-A treatment there were 3.88 fewer incontinence episodes per day, but a ninefold increased odds of increased PVR after treatment was also noted.41 Intravesical injections of BoNT-A improved the HRQL in patients with IDO and NDO.42 Patients who received repeated doses did not seem to become refractory to BoNT-A.43 Recent studies have shown that BoNT-A is also effective in the treatment of urinary incontinence in children.44,45 However, the high rate of increased PVR that requires CIC after treatment remains a problem to be solved. Therefore, further robust data are required on long-term outcomes, safety and the optimal dose of BoNT-A for OAB.46
What is the optimal dose of BoNT-A for OAB or IDO
In a review of previous studies using BoNT-A for IDO, most investigators used 200 U or 300 U detrusor injections. Sahai et al. evaluated the efficacy of 200 U onabotulinumtoxinA detrusor injection for patients with IDO and found the therapeutic effect lasted for 6 months; however, among the patients, 33% required clean intermittent catheterization to evacuate PVR.47 Jeffery et al. used 500 U abobotulinumtoxinA in treating patients with IDO and found that 32% remained continent at 6 months, whereas 35% of patients required CIC at 3 months and 22% still required CIC at 6 months.48 Kessler et al. treated 11 patients with IDO with 300 U onabotulinumtoxinA detrusor injections and the maximal bladder capacity increased from 220 to 340 mL; however, four of the patients required CIC as a result of large PVR.34 Rajkumar et al. treated 15 IDO women with 300 U onabotulinumtoxinA detrusor injections, and 14 of the patients had an improvement in urgency and frequency; the therapeutic effects lasted for 5–6 months.35 Popat et al. used 200 U onabotulinumtoxinA for 31 IDO patients; although significant improvement of bladder capacity was noted after treatment, 20% of the patients required CIC.36 Schulte-Baukloh et al. used 300 U of onabotulinumtoxinA detrusor and urethral injections for seven women with OAB without DO; the bladder capacity increased by 20% and all patients could void without the need of CIC.10 Kuo found that detrusor injections of 200 U onabotulinumtoxinA provided a 73.3% success rate in 30 IDO patients; the mean therapeutic duration was 5.3 months,9 whereas suburothelial injections of 200 U onabotulinumtoxinA provided an 85% success rate for IDO patients (Fig. 1b).37
When comparing 200 U, 150 U and 100 U of onabotulinumtoxinA, Kuo found that 100 U can also have an excellent therapeutic effect on IDO (73.3%) compared with the results of 200 U detrusor injections.38 Recently, the dose of onabotulinumtoxinA for IDO was further reduced to 100 U by many investigators, and still a satisfactory outcome of approximately 53–88% was achieved.38–40 Several recent multicenter placebo controlled studies also showed that onabotulinumtoxinA at doses of 100 U was well tolerated, and had durable efficacy in the management of IDO and UUI without increasing adverse events.49,50 OnabotulinumtoxinA doses of more than 150 U were more commonly associated with PVR volume of more than 200 U.51 Intravesical BoNT-A injections were also shown to be effective in patients with refractory OAB without DO.10,52 However, although repeated 100 U onabotulinumtoxinA injections are safe and effective in treating patients with OAB, certain patients will benefit from dose optimization to improve efficacy or prevent voiding dysfunction.53
Adverse events after BoNT-A for OAB
Although clinical efficacy of BoNT-A on IDO has been largely confirmed, the high incidence of adverse events remains a problem to be solved. Kuo found that urinary tract infection occurred in 35% of patients, a large PVR requiring CIC in 30% and difficult urination in 75% of patients with IDO who received 200 U suburothelial onabotulinumtoxinA injections.37 Brubaker et al. found that approximately 60% of women had a clinical response, but 43% developed increased PVR and 75% of these developed UTI after detrusor injections of 200 U onabotulinumtoxinA.54 This high incidence of adverse events might prohibit patients from receiving a second injection when their LUTS relapse. If the dose of suburothelial onabotulinumtoxinA is reduced to 100 U, the rates of adverse events will reduce to 4.3% of urinary tract infection, 30.4% of a large PVR and 56.5% of difficult urination.38 Dose-dependent adverse events were further confirmed by Dmochovski et al., where doses of onabotulinumtoxinA greater than 150 U contributed minimal additional or clinically relevant improvement in symptoms, whereas the adverse event of large PVR requiring CIC was greater than with a 100 U injection. Based on this multicenter placebo control trial, a dose of 100 U onabotulinumtoxinA was recommended as optimal for treating refractory OAB.47
In a retrospective analysis of adverse events occurring after intravesical injections of 100 U onabotulinumtoxinA, Kuo found that the occurrence of adverse events was high after BoNT-A injection for patients with IDO. Figure 2 shows the changes of bladder capacity, Qmax, PVR, Pdet and voiding efficiency from baseline to 12 months after 100 U onabotulinumtoxinA injection in patients with OAB. Bladder capacity and PVR increased to a maximum and voiding efficiency decreased to a minimum at 1 month, then slowly returned to baseline levels within 12 months.55 More than 40% of patients developed large PVR (>150 mL) and needed straining to void, and 6.9% of patients had AUR during the first 3 months after treatment. Male sex and baseline PVR ≥100 mL, comorbidity, and onabotulinumtoxinA doses of more than 100 U are risk factors for increasing incidence of adverse events.55 However, the occurrence of these BoNT-A related adverse events did not affect the likelihood of successful outcome. Kuo et al. also found that patients with the occurrence of large PVR and straining to void after intravesical 100 U onabotulinumtoxinA injection had significantly higher success rates at 3 months, and the long-term success rate was not significantly different between patients with and without these adverse events.56 However, patients usually could accept the adverse events of difficult urination and increased PVR in exchange of the reduction of urgency or UUI, suggesting a lower detrusor contractility is necessary for the therapeutic effect of BoNT-A injection.55
In fact, not all patients with OAB can benefit from BoNT-A injections. The overall success rate was found to be approximately 70%.9,37,38,55,57 Patients might have both sensory and motor improvements, or only sensory or motor effects. Reduction of urgency severity is associated with a long-term therapeutic effect after intravesical BoNT-A injection for IDO.58 Injection site seems to have little effect on therapeutic outcome. Bladder base and trigonal injections fare the same safety and efficacy as bladder body injections with or without trigone involvement.59 In an analysis of the baseline parameters, Kuo also found that baseline parameters of IDO patients, except the subtype of DO, do not predict the treatment outcome.60
Whether trigone injections of BoNT-A can improve the therapeutic effects of OAB has been discussed. The urinary bladder is rich in sensory fibers, but their role in bladder urgency sensation and IDO has not been explored. Sensation from the trigone in these patients might be more closely related to early bladder filling rather than bladder wall stretch at capacity. Hence, treatment aimed at reducing sensation from the trigone might not improve urgency sensation, which occurs at phasic contractions during bladder filling. Significant increases in cystometric capacity and PVR compared with baseline were found in the bladder body injections, but not in the bladder base and trigone group. Bladder base BoNT-A injection relieved urgency sensation, but could not increase bladder capacity. Compared with bladder body injections, the bladder base and trigonal BoNT-A injections have been found to have a lower success rate at 6 months in patients with IDO.61 However, another study showed that if BoNT-A injections involved the trigone and bladder body (trigone-including), injections of 500 U abobotulinumtoxinA were found superior to the trigone-sparing group for the treatment of refractory IDO, and did not cause vesicoureteral reflux.62
Although VUR might be a potential complication after BoNT-A injections in these areas, there is no evidence in the recent studies so far to prove its presence.61–63 An advantage of trigonal injection of BoNT-A is the freedom of detrusor underactivity developing after treatment.60 Another interesting finding in trigonal BoNT-A injection is the reduction of the incidence of autonomic dysreflexia in SCI patients with NDO and DSD.64 Trigonal BoNT-A injection might decrease sensory input from this area and reduce bladder hypersensitivity in patients with dry OAB.
BoNT-A for neurogenic voiding dysfunction
DO and DSD commonly occur in patients with suprasacral cord lesions, such as SCI, MS or transverse myelitis. The presence of DSD is associated with complete injuries, elevated intravesical pressures and upper tract complications.65 Patients with DSD usually suffer from urinary incontinence and large PVR requiring CIC or indwelling a Foley catheter. These urological complications usually result in a low QoL, and might cause more serious complications, such as AD, UTI or upper urinary tract deterioration.66 In 2011, detrusor injections of 200 U onabotulinumtoxinA were approved by the Federal Drug Administration of USA for treatment of NDO as a result of SCI and MS.
Effects of BoNT-A on NDO
In recent decades, the treatment of DO and DSD with BoNT-A has emerged as an alternative method for the management of urological complications as a result of spinal cord lesions. Detrusor injection of 200–300 U of onabotulinumtoxinA can reduce detrusor contractility, improve bladder compliance and restore urinary continence in patients with NDO (Fig. 1c).8,67 BoNT-A is found to modulate afferent activity of the bladder in association with reduced DO and OAB symptoms in NDO patients.68 In a chronic SCI rat model, intravesical BoNT-A significantly inhibited the afferent response without impairing efferent bladder function.69 However, clinically this treatment usually induces impaired detrusor contractility, large PVR or urinary retention in NDO; approximately 70% of patients require periodic CIC, and subsequent UTI could become a de novo problem.70
BoNT-A toxin treatment of DO as a result of spinal cord lesion has been reported to provide satisfactory results.71,72 Detrusor underactivity will develop after detrusor injection of 300 U of onabotulinumtoxinA, and the urodynamic and QoL parameters improvements last for 9 months.73 A total of 73% of patients treated for neurogenic bladder can resume a continent condition after treatment.70 The results seem promising for achieving urinary continence and to increase bladder capacity. Repeated detrusor BoNT-A injections for refractory NDO in patients with SCI or MS have a consistent effect on bladder control.72,74 Recent study further revealed 100 U onabotulinumtoxinA intradetrusor injection for MS seems to be effective and safe. Most patients can void voluntarily without compromising voiding efficiency.75 In patients with Parkinson's disease and refractory DO, intradetrusor injection of 100 U onabotulinumtoxinA also induced clinical and urodynamic improvement in OAB that lasts for 6 months.76,77
Schurch et al. compared detrusor injections of 200 U and 300 U onabotulinumtoxinA to placebo in treating NDO in SCI patients. The QoL index showed no significant difference between 200 U and 300 U, but both doses showed significantly better therapeutic outcome than that in the placebo group.71 Grosse et al. compared the interval between repeated detrusor BoNT-A injections and found repeat BoNT-A injections are as effective as the first one. The intervals between repeated BoNT-A injections did not significantly different between one to two injections, two to three injections and three to four injections. However, the clinical and urodynamic parameters were significantly decreased at months 6–9, suggesting repeat injections were required by this time-point.72
Recent randomized, double-blind, placebo control trials of BoNT-A on NDO showed that BoNT-A has a benefit in both SCI and MS patients with NDO. BoNT-A significantly reduced UI, and improved urodynamic parameters and QoL in MS and SCI patients with NDO. Both doses of 200 U and 300 U onabotulinumtoxinA were well tolerated, with no clinical relevant differences in efficacy or duration of effect.78 Interestingly, the trigone-including BoNT-A injections were found to have significant superiority to trigone-sparing injections for NDO in both incontinence episodes and urodynamic parameters.79
Urethral or detrusor BoNT-A injections for DSD?
Patients with DSD usually have both storage and empty symptoms. Some of the patients with DSD have to carry out CIC by themselves or with the help of a caregiver, in addition to voiding by abdominal tapping. However, some patients with DSD prefer spontaneous voiding without instituting CIC, and some might prefer being dry after treatment although CIC is necessary. Therefore, management of voiding dysfunction and incontinence in patients with SCI and DSD is a challenge to physicians, and should be considered an art-of-the-medicine. Although BoNT-A treatments have been shown to be effective in reducing incontinence in patients with spinal cord lesion and DSD, patients might have too high expectations of the therapeutic effects of BoNT-A before treatment. Furthermore, some patients might be disappointed by the development of de novo problems that they do not anticipate, and are likely to have a low rate of satisfaction with BoNT-A treatment.
Approximately 95% of patients with suprasacral lesions demonstrated DO with or without DSD.80 Hand dexterity, abdominal muscle power, bladder sensation and the degree of urethral sphincter dyssynergia might affect the voiding efficiency and LUTD.65 Treatment of DSD and improvement of QoL have many aspects, including medical or surgical procedures; however, most types of management cannot achieve a high success rate. In the era of BoNT-A, it is possible to use detrusor injection to decrease detrusor contractility,70,71 urethral injection to reduce urethral resistance7,15 or to combine detrusor and urethral injections to achieve the desired goals.81 Reduction of DO can decrease urinary incontinence, whereas reduction of urethral resistance can decrease PVR.
Although intradetrusor BoNT-A injections for NDO can increase bladder capacity and achieve urinary continence, most patients still have to carry out CISC or require a caregiver to carry out CIC to empty their bladder periodically. This management is usually satisfactory for patients with SCI and NDO, but might not be widely used in developing countries where public services for CIC are lacking. Patients who do not have access to facilities or resources for CIC would prefer spontaneous voiding and wearing an external appliance without requiring CIC. In order to achieve improvement of incontinence, decrease urgency episodes and retain spontaneous voiding function, a lower dose of BoNT-A for detrusor injection could provide a satisfactory result to the majority of patients with spinal cord lesions and DSD.82
Satisfaction and dissatisfaction to detrusor BoNT-A injections for NDO
In a study evaluating the therapeutic satisfaction and dissatisfaction in patients with spinal cord lesions and DSD who received detrusor BoNT-A injections, complete dryness was welcomed by 58%, but 12% of patients were bothered by persistent incontinence and 10% still considered difficult bladder emptying and the need for CIC as dissatisfaction with the treatment (Table 2).83 The dose of 200 U onabotulinumtoxinA in that study might not be adequate for patients who wish to become completely dry, as shown in the 12% of patients in that study, possibly as a result of inadequate dose of BoNT-A for their DO. For these patients, a dose of 300 U onabotulinumtoxinA or more might be necessary to achieve urinary continence. Nevertheless, with 200 U of onabotulinumtoxinA, most patients can achieve an improvement in incontinence episodes and preserved spontaneous voiding.
Table 2. Main therapeutic effects of lower urinary tract dysfunction and causes for dissatisfaction with detrusor BoNT-A treatment
Main therapeutic effects of LUTD
Causes of dissatisfaction to treatment
Just seven patients presented with symptoms of autonomic dysreflexia at baseline.
Treatment of NDO and DSD might also be different between sexes. Female patients with SCI and DSD usually have more severe urinary incontinence and require diaper protection. Because carrying out CIC requires more facilities and resources for women, women with SCI and DSD would prefer to be dry and not have a diaper. On one hand, male SCI patients can use an external appliance to collect urine and prevent urine soiling, therefore, the desire to become dry is not as high as that in female SCI patients. On the other hand, male SCI patients might not appreciate being completely dry and requiring CIC after detrusor BoNT-A injection; in that case, a small dose of BoNT-A, for example 200 U of onabotulinumtoxinA, would be an adequate dose to increase bladder capacity and allow patients to void by abdominal tapping.
Therapeutic effects of Botox on IC/PBS
IC/PBS is a debilitating chronic disease of unknown etiology characterized by urgency frequency and suprapubic pain at full bladder. Current treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity in patients with IC/PBS.84 Various therapy options including oral pentosan polysulphate, cyclosporine A, amitriptyline, and intravesical heparin, hyaluronic acid and bacillus Calmette-Guérin, resiniferatoxin have not shown long-term effects.85–88 Intravesical injection of BoNT-A has been introduced to treat IC/PBS, although its use in LUTD remains unlicensed. Small-scale studies suggested that the short-term efficacy of a single injection of BoNT-A seemed promising with acceptable adverse events. However, the long-term effects of repeated BoNT-A injection need to be elucidated. In addition, the method of administration (i.e. dose, volume and site of injection) still requires further determination.
Pathophysiology of IC/PBS
The unreliable effective therapy for IC/PBS is possibly a result of poorly understood pathophysiology. Recent findings suggest several pathophysiological mechanisms, including epithelial dysfunction, activation of mast cells, neurogenic inflammation, autoimmunity and occult infection, are involved in IC/PBS.89 One of the most common findings in bladder mucosal biopsies from IC/PBS patients is denudation or thinning of the bladder epithelium, suggesting altered regulation of urothelial homeostasis.90 Other bladder abnormalities include increased nerve fiber density and inflammatory cell infiltration.91–94 Although investigations have been enthusiastically carried out, the etiology of IC/PBS remains unknown. The loss of epithelial integrity is believed to be a predominant histopathological finding. Epithelial damage might precede the other histopathological findings in the bladder wall.95 The suburothelial space immediately below the basal lamina is well supplied with sensory nerves that transmit the sensation of bladder fullness and respond to bladder inflammation.96,97 A local inflammatory process might be induced through the afferent and efferent nerves in the suburothelial interstitial cellular network that integrate the transmission of signals from the urothelium to the detrusor muscles in the bladder wall.98
In a rat chemical cystitis model, a detrusor injection of BoNT-A increased bladder capacity and compliance.99 In other basic research, BoNT-A inhibited the release of acetylcholine, norepinephrine, NGF, ATP, substance P and calcitonin gene-related peptide from the nerve fibers and urothelium.30,100–102 Furthermore, in a recent study using a cyclophosphamide-induced cystitis model, Chuang et al. showed that intravesical BoNT-A administration could inhibit cyclooxygenase 2, and EP4 expression and suppress bladder hyperactivity in rats.103 In clinical and animal experiments, BoNT-A has been shown to reduce DO, impair bladder sensation and decrease visceral pain in chronic inflammatory diseases.12,37,104 These results suggest that BoNT-A treatment can modulate sensory and motor transmission, as well as reduce bladder inflammatory conditions. It is also possible that the chronic symptomatology in bladder hypersensitivity is a result of central sensitization and persisting abnormality or activation of the afferent sensory system.105 In this regard, inhibition of neuroplasticity of the sensory fibers in the suburothelial space by intravesical BoNT-A injections might have good therapeutic targeting for pain and sensory urgency in patients with IC/PBS.106
Efficacy of BoNT-A on IC/PBS
Pilot studies reporting the efficacy of BoNT-A for treating IC/PBS since 2004 have revealed controversial results.12,107,108 However, most recent studies support the effects of BoNT-A in patients with chronic IC/PBS.108–116 All nine articles mentioned in Table 3 reporting the use of BoNT-A for IC/PBS utilized onabotulinumtoxinA. Of these, one study was level 1 and two were level 2. One of the level 2 studies compared 100 U or 200 U onabotulinumtoxinA with hydrodistention versus hydrodistention alone.110 At 3 months, there was a significant decrease in symptom indices, symptoms recorded in a bladder diary and urodynamic parameters with onabotulinumtoxinA compared with hydrodistention alone. The other level 2 study showed more improvement in frequency, nocturia and global IC score with 300 U of onabotulinumtoxinA compared with instillation of bacillus Calmette-Guérin.111 The level 1 study reported on QoL outcomes utilising the Chronic Prostatitis Symptom Index (female modification) and American Urological Association indices, as well as graded chronic pain, and perceived stress scales and the VAS; outcomes were not found to be significantly different from a placebo.109 The authors emphasized that adjustment of the given dose, dilution method and injection site might require further refinement.
Table 3. Data for the use of BoNT-A in interstitial cystitis/painful bladder syndrome
Administration: Technique, site and volume of injection for IC/PBS
Different injection depths (i.e. superficial muscle vs suburothelial) and various injection sites (whole bladder, trigonal or periurethral) have been reported for application of BoNT-A. All nine studies in Table 3 used suburothelial injections for the treatment of IC/PBS. Of these, four included the trigone and one injected around the bladder neck. The volume varied from 2 mL to 30 mL in 10–40 injection sites. The method of administration clearly requires further study.
Adverse events of BONT-A treatment for IC/PBS
Gottsch et al. injected 50 U of onabotulinumtoxinA into the bladder neck and found no systemic or local complications.109 In contrast, Kuo and Chancellor reported two of 15 patients had hematuria, seven had dysuria and five with a large PVR after receiving 200 U of onabotulinumtoxinA.110 It must also be noted that patients received hydrodistention with onabotulinumtoxinA, but the incidence of hematuria and large PVR was 0%, and 4% developed dysuria after hydrodistention alone.
Long-term efficacy of BoNT-A on IC/BPS
Although BoNT-A injection seems promising in treating symptoms of IC/PBS, long-term results have not shown successful outcomes. Giannantoni et al. reported a 1-year follow up of 15 IC/PBS patients receiving BoNT-A injection therapy. A total of 13 of these patients (86.6%) reported subjective improvement at the 1-month and 3-month follow ups. At 5 months, the beneficial effects persisted in 26.6% of cases, but frequency, nocturia and the pain VAS had increased. At 12 months, pain had recurred in all patients.112 Kuo et al. showed long-term results with repeated BoNT-A injections every six months in 71 patients with refractory IC/PBS for up to four injections.117 Among them, 71, 49, 32 and 19 patients completed one, two, three and four intravesical BoNT-A injections, respectively. As the number of treatments increased from one to four, the IC/PBS symptom score, pain VAS and daytime frequency significantly decreased. When the BoNT-A injection was repeated up to four times, functional bladder capacity, volume at full sensation and cystometric bladder capacity significantly increased. In addition, a successful result (change of Global Response Assessment scores ≥2) at 6 months after the first, second, third and fourth BoNT-A injection was reported in 24 (44%), 15 (44%), nine (53%) and seven (54%) patients. The overall incidences of adverse effects including UTI, dysuria, intermittent catheterization, acute urine retention and hematuria during the first, second, third and fourth treatments were 28%, 29%, 45% and 32%, respectively.
In comparison with studies of BoNT-A for treatment of other LUTD, the studies of this drug for treatment of IC/PBS were relatively fewer, smaller scaled and lower evidence-based level. Intravesical injection (with or without trigone involvement) of BoNT-A seems effective in reducing daily frequency, nocturia and pain VAS, and improving functional bladder capacity, maximum cystometric capacity and QoL in IC/PBS patients in the short-term. The long-term efficacy of repeated BoNT-A for treatment of IC/PBS and the optimal administration method require further confirmation.
BoNT-A on LUTS/BPH
BPH is a common cause of voiding dysfunction in men. Medical treatment by combining α1 adrenergic antagonists and 5ARI inhibitors is currently effectively used to relax the urethral smooth muscle and shrink the prostatic glandular component.118–120 Some patients who receive the combined 5ARI and alpha-blocker medical treatment still experience clinical BPH progression or have only limited improvement in the condition.120,121 Such patients might have a low QoL as a result of bothersome LUTS that might lead to surgical intervention.
Mechanism of action of BoNT-A on BPH
Previous studies established that the prostatic epithelium receives a cholinergic innervation, whereas the stroma receives a predominantly noradrenergic innervation.122,123 Recent investigations also suggest that BPH could originate from neural dysregulation of the prostate and alterations in local neuropeptides.124 BoNT-A has been shown to block the release of neurotransmitters from the presynaptic nerve terminal including acetylcholine, norepinephrine, CGRP, substance P and glutamate.125,126 Injection of BoNT-A in the prostate provides an alternative treatment for patients with symptomatic BPH, especially those who are at high surgical risk.127
Previous studies using rat models provided direct evidence that intraprostatic injection of BoNT-A induces selective denervation, and subsequent apoptosis and atrophy of the glands.128,129 Injecting BoNT-A into dog prostate reduced contractile function while maintaining the relaxation response of the prostate.130 The prostate atrophy induced by BoNT-A injections in rats is likely the result of sympathetic nerve impairment and a decrease of adrenergic stimulation of the gland.131
Previous clinical trials have shown that BoNT-A has durable therapeutic effects in relieving LUTS in patients with small BPH of smaller than 30 mL.132 Another previous study showed that intraprostatic injection of 200 U onabotulinumtoxinA reduced approximately 50% of the total prostate volume in BPH patients with large prostates and improved LUTS from 1 month after injection, and the effect persisted at 12 months.11 However, other studies failed to confirm these therapeutic effects.127,132 Silva et al. injected 200 U onabotulinumtoxinA into the prostate of patients with BPH and refractory urinary retention, and found 81% of them could resume voiding at 3 months. The mean prostate volume decreased from 70 mL to 57 mL at 1 month, and to 47 mL at 3 months.133 The duration of prostatic volume reduction was found to last for a period of 18 months after a single intraprostatic injection of 200 U onabotulinumtoxinA.134 Risinda et al. found 55 of 77 patients (71%) had subjective symptomatic improvement after intraprostatic injection of 200 U onabotulinumtoxinA; however, the prostatic volume reduced by just 12.7%.135
Injection technique of BoNT-A in the prostate
Prostatic injections of BoNT-A can be carried out transperineally, transrectally or transurethrally.127,132 Among these three ways, transperineal injection provides the best way of approach and is free of the risk of UTI.132 However, transrectal prostatic injection is the procedure that urologists are most familiar with. During treatment, onabotulinumtoxinA 200 U is reconstituted by normal saline to a volume of 20% of total prostate volume, and is injected transperineally or transrectally to the transition zone and peripheral zone under 2% lidocaine local anesthesia at an outpatient clinic or under intravenous general anesthesia in the operation room. The injection needle should be inserted as deep as possible, but not penetrating into the urinary bladder. Under transrectal sonography guidance, the prostatic gland is adequately distributed by the injecting solution with the volume (Fig. 1d). BoNT-A solution should be injected equally to bilateral lobes, including the median lobe. Broad-spectrum antibiotics should be routinely prescribed for 3 days to prevent prostatic infection after injections.
After prostatic BoNT-A injections, a certain percentage of patients might develop adverse events such as gross hematuria, difficult urination, perineal pain, or acute prostatitis. These adverse events are caused by inadvertent penetration of the injection needle through the prostatic urethra in patients with asymmetry of the prostatic lobes, volume effect of the injected volume or inadequate sterility procedure. Careful inserting the needle under sonographic guidance, small injecting volume and adequate sterility can usually reduce these adverse events to a minimum.
Although clinical results of intraprostatic BoNT-A injections for BPH seem promising, a report from a large scale, randomized, placebo-controlled clinical trial has not come out yet. An enlarged prostate consists of a variable proportion of a glandular component, fibrous tissue and smooth muscles.136 The glandular component comprises just 20–40% of the total prostate volume.137 Whether intraprostatic injection of BoNT-A can reduce the prostatic volume by more than 20% is still questionable. Using 5ARI to reduce prostatic hyperplasia, the total prostatic volume reduction was estimated to be 15–20% in long-term treatment.119 If BoNT-A has an effect on glandular apoptosis, the volume reduction of total prostate volume will be, at most, the same extent of that by 5ARI.
Kuo et al. carried out a clinical study of adding-on BoNT-A in patients with large BPH (>60 mL) and unsatisfactory response to combined medical therapy with alpha-blocker and 5ARI.138 They found that add-on BoNT-A prostatic injection provided no significant therapeutic benefit to patients. Although BoNT-A prostatic injections had a short-term effect in improvement of clinical BPH parameters, the long-term therapeutic effect was similar to that of the patients who continued medical treatment. Nevertheless, BoNT-A prostatic injection treatment was safe, but with minor adverse effects including hematuria, acute urinary retention and acute prostatitis. The results of that study did not support previous reports and showed add-on BoNT-A treatment provides limited clinical effect in patients with LUTS and BPH larger than 60 mL.
Controversy of BoNT-A treatment for BPH
Based on these clinical studies, patients receiving BoNT-A injections showed an early decrease of prostate volume and an improvement of flow rate, indicating that BoNT-A can be an effective and rapid treatment of BPH through the possible mechanisms of induction of glandular atrophy or smooth muscle degeneration. However, the therapeutic outcome of BoNT-A therapy might not maintain and the long-term result is similar to continuing medical therapy, suggesting BoNT-A might not produce a durable effect of prostatic glandular atrophy in large BPH in the long term.
Previous studies of the effect of BoNT-A on men with small BPH have shown a durable effect on LUTS improvement without a remarkable decrease of prostate volume.133 In fact, the prostatic volume is not well correlated with urethral resistance, as aging men with a small prostate might have a high bladder outlet resistance and LUTS.139 In contrast, LUTS in men are not solely caused by BPH obstruction. The causes for non-BPH LUTS in these patients could be increased bladder sensation, DO or urethral dysfunction.140 In patients with a total prostate volume of less than 40 mL or 30 mL, the incidence of BOO is just 75% or 50%, respectively.141 In other words, LUTS might not be caused by BPH in a large number of patients with small BPH. The enlarged prostate could be an innocent bystander in patients with LUTS and a small BPH.
The main therapeutic effect of BoNT-A on LUTS in patients with small BPH might not from reduction of prostate volume, but through urethral muscle paralysis or suburethral neuromodulation without actually decreasing the glandular component of the prostate. Urethral sphincter injection of BoNT-A has been shown to reduce urethral resistance in patients with spastic urethral sphincter or isolated urethral sphincter obstruction.15 The effect of BoNT-A on small BPH and LUTS might be a result of reduced urethral resistance by affecting the urethral muscles rather than affecting the prostate glands. Therefore, in patients with large BPH receiving transperineal BoNT-A injections, the BoNT-A effect on the reduction of prostate volume was not remarkable and cannot have a long-term effect.
Based on the currently available data, BoNT-A might not be considered as the first-line therapy for large BPH. However, because a short-term BoNT-A effect still can be achieved, prostatic BoNT-A injection can be used as an adjuvant therapy for patients who have an unsatisfactory response to long-term medical treatment and require urgent treatment for refractory urinary retention, especially in elderly patients unfit for surgical intervention.