Botulinum's Role in Urology Grows
The use of botulinum toxin (BTX) for various non-urological indications, such as cervical dystonia, blepharospasm, and strabismus has been well accepted for more than a decade, but its application in urology has been somewhat slower in developing. Some of the original descriptions of the use of botulinum toxin in urology date back nearly 20 years, when it was first used to treat detrusor sphincter dyssynergia.
Since then, applications for neurogenic overactive bladder (OAB), idiopathic OAB, pelvic pain syndromes, and prostate-related lower urinary symptoms have been described, as have pediatric uses.
Seven distinct antigenic subtypes of botulinum toxin have been de-scribed, only two of which (A and B) are commercially available. Botulinum type A has undergone the most clinical testing in urology, and of the type A preparations, only Botox is currently available in the United States. Dysport, a less potent formulation of BTX type A, has been available overseas, primarily in the United Kingdom, for several years.
Historically, the mechanism of action of BTX has been linked to its uptake at the presynaptic nerve terminal and to its ability in preventing synaptic vesicle fusion and acetylcholine release at the neuromuscular junction. More recently, it has been speculated that other mechanisms of action, such as an impact on neurotransmission affecting sensory perception, may be also partially responsible for some of its encouraging clinical findings.
At total doses ranging from 50-300 U, BTX has been shown to be effective in decreasing urinary frequency, urgency, and urge incontinence episodes in both neurogenic and idiopathic OAB. Typically injected at 10 U per site and with the number of sites typically ranging from 20-30, BTX is generally well tolerated when injected in an office-based setting after the instillation of a local anesthetic intravesically, though initial studies used injections administered under spinal or general anesthesia.
The injection technique (rigid versus flexible cystoscopy), location (including the trigone versus excluding it), and total dose (typically 50-200 U for idiopathic OAB and 200-300 U for neurogenic OAB) have varied between studies.
Overall, most studies of patients with refractory idiopathic OAB symptoms have shown durable improvements (at least six months) in total bladder capacity (increases greater than 50%), pad usage (decreases of 50%), and urge incontinent episodes (Eur Urol. 2005;48:984-990). Urodynamic improvements (increases in maximum capacity and volume at first overactive contraction, as well as reductions in peak detrusor pressure) have been noted in most studies.
A multicenter study of patients with neurogenic OAB randomized to injection with either saline or 200 or 300 U of BTX noted significant improvement in symptom scores persisting at six months in conjunction with the expected urodynamic changes in each of the active treatment arms (J Urol. 2005;174:196-200).
Concerns over the efficacy of repeat injections have been voiced, due primarily to the possibility of bladder scarring or the development of anti-BTX antibodies, though re-cent data suggests that, even after five injections, efficacy appears to be maintained (Urology. 2006;68:1193-1197).
Safety issues have been raised regarding the use of BTX for OAB. The risk of systemic manifestations of BTX injection appears to be minimal in the several small studies published, with very few, if any, systemic toxicities noted. A risk of elevated residual and significant voiding dysfunction may indeed be present, but it remains relatively poorly defined.
Most studies seem to indicate a fairly low incidence of voiding dysfunction with injections of 100 U or less in patients without pre-existing voiding abnormalities. At this point, it seems most prudent to inform all patients about the possibility of the need for transient intermittent catheterization until results of larger, multicenter, dose-ranging studies become available.
Detrusor sphincter dyssynergia
BTX injections into the external urethral (rhabdo) sphincter have been used to treat neurogenic voiding dysfunction secondary to DSD. Both transperineal and transure-thral injection techniques have been described in men; periure-thral injections have been used successfully in women as well.
A randomized study comparing saline injections to 100 U of BTX in patients with MS and DSD noted significant increases in voided volumes (60%) and decreases in voiding pressures (21%) among patients receiving active treatment compared with placebo (J Neurol Neurosurg Psychiatry. 2005;76:1670-1676).
Efficacy appears to be similar among patients with spinal cord injury (SCI), and the overall durability of BTX when injected for DSD appears to be approximately four to six months. Among patients with significant neurogenic voiding dysfunction who may be at risk for upper-tract damage due to elevated intradetrusor pressures, BTX therapy offers the hope of lowering outlet resistance and improving voiding without the permanent impact of surgical sphincterotomy.
While not thoroughly studied, the idea of simultaneous detrusor and sphincter injections of BTX has been suggested to treat simultaneous DO and DSD.
In addition to affecting acetylcholine release, BTX appears to have nociceptive effects by inhibiting the release of neurotransmitters involved in sensory perception, such as substance P and glutamate. As a result of these properties, BTX has been used to treat pelvic pain syndromes, though data are somewhat limited.
Overall, the impact of BTX on interstitial cystitis symptoms has been mixed, with one study noting significant improvements after intradetrusor injections (Urology. 2004;64:871-875), whereas a second study comparing two different means of instillation (in-travesical instillation versus more classic intradetrusor injections) revealed no change in symptom scores (Urol Clin North Am. 2005;32:89-99).
Among patients with chronic pelvic pain, BTX injections into the levator and in women (Aust N Z J Obstet Gynaecol. 2004;44:46-50) and into the prostates of men (Eur Urol. 2000;38:393-399) have resulted in fairly durable improvements in symptom scores in non-placebo-controlled studies.
Recently, enthusiasm has emerged for the use of prostatic injections of BTX for relieving lower urinary tract symptoms (LUTS) attributable to benign prostatic enlargement in men. Using injections of 200 U of BTX, symptom score improvements of 50% or better have been noted along with similar improvements in quality of life scores (Urology 2005;66:775-779).
These improvements in LUTS symptom score ap-pear to persist for six to 12 months. Interestingly, reductions in prostate size of up to 30% have been observed following a single BTX injection, suggesting that improvements in symptom score in part might be a result of a reduction in mechanical outlet obstruction rather than either an alteration in sensory perception or prostatic smooth muscle relaxation (Urology. 2005;65:670-674).
Like most other initial work with BTX, this finding awaits corroboration of larger multicenter trials to further delineate the possible mechanism of action, and clarify the safety profile, durability, and overall efficacy.
As data emerge from large multicentered clinical trials of BTX for neurogenic and non-neurogenic refractory OAB, urologists will learn more about the potential benefits of this new therapy. Meanwhile, although it does not appear as though BTX will replace the traditional role of anti-muscarinics in the treatment of OAB, it is certainly logical to consider BTX as an alternative treatment option, particularly if the efficacy rivals that of oral agents and durability remains consistent over time.
Further, it seems quite likely that other urologic indications, mentioned above in the context of single institution experiences, also will be explored in large-scale trials. It certainly does not seem far-fetched to foresee a day where neurotoxins, such as botulinum toxin, play an important role in the treatment of disorders involving the lower urinary tract and pelvic floor in both men and women.Dr. Lemack is associate professor of urology at the University of Texas Southwestern Medical Center in Dallas.