Urologic applications of botulinum toxin

OFF-LABEL UROLOGIC INDICATIONS

Botulinum toxin injection has been studied off-label for painful bladder syndrome/interstitial cystitis and for chronic prostatic pain. Patients with these conditions often describe pain with filling of the bladder, which leads to urinary frequency in an attempt to relieve the pain.

These pain syndromes can be difficult to treat and can have a devastating impact on quality of life. Treatment options include pain management, stress management, physical therapy, intravesical therapies, cystoscopy with hydrodistention, neuromodulation, cyclosporine, urinary diversion surgery, and botulinum toxin injection (an off-label use).³¹

In painful bladder syndrome/interstitial cystitis, botulinum toxin is thought to act on sensory afferent pathways, as well as to inhibit the release of substance P and glutamate, neuropeptides involved in sensory and nociceptive pathways.⁶ In animal studies,³² botulinum toxin was found to inhibit the afferent neural response by inhibiting mechanoreceptor-mediated release of adenosine triphosphate and by causing a decrease in calcitonin gene-related peptide, which helps regulate micturition and mediates painful bladder sensation.

Clinical studies to date in pelvic pain syndromes

Data from clinical studies of botulinum toxin injection for pelvic pain syndromes are limited. Zermann et al³³ performed transurethral perisphincteric injection in 11 men with chronic prostatic pain, 9 of whom reported subjective pain relief, with an average decrease from 7.2 to 1.6 on a visual analogue scale. Postinjection urodynamic studies showed a decrease in functional urethral length, urethral closure pressure, and postvoid residual volume, and an increase in the peak and average flow rates.³³

Abbott et al³⁴ evaluated the effect of botulinum toxin injection into the levator ani in 12 women with chronic pelvic pain and pelvic floor hypertonicity. Pelvic floor manometry showed significant reduction in resting muscle pressures and improvements in dyspareunia and nonmenstrual pain. There were also improvements in quality of life and dyschezia, but these were not statistically significant.

Smith et al³⁵ injected botulinum toxin into the detrusor of 13 women with refractory painful bladder syndrome and interstitial cystitis,³⁵ and 9 women (69%) noted statistically significant improvements in the Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index, daytime frequency, nocturia, pain, and urodynamic parameters (volume at first desire to void, and maximum cystometric capacity).

In a prospective randomized study of patients with refractory painful bladder syndrome and interstitial cystitis, Kuo and Chancellor³⁶ compared suburothelial injection of 200 U or 100 U of botulinum toxin plus hydrodistention against hydrodistention alone.Patients who received botulinum toxin had increased bladder capacity and improved long-term pain relief, but no difference was noted between 200 U and 100 U, and more adverse effects were seen with the higher dose.³⁶

Pinto et al³⁷ treated 16 women with refractory painful bladder syndrome and interstitial cystitis with intratrigonal injections of botulinum toxin and reported improvements in pain scores, symptom scores, urinary frequency, and quality-of-life measures. The effect lasted 9.9 months (± 2.4 months) and persisted with successive injections.³⁷

More study needed

Although these studies show that botulinum toxin injection for pelvic pain syndromes has the potential to improve pain, urinary frequency, bladder sensation, bladder capacity, and quality of life, larger randomized controlled trials are needed.

Again, the treatment options are limited for refractory painful bladder syndrome and interstitial cystitis. Patients may be desperate for relief from their symptoms. Practitioners must manage expectations and properly inform patients of the potential risks of treatments, especially with patients who will easily agree to further treatment with the smallest hope of relief.

INJECTION TECHNIQUES

For general points about the procedure to discuss with patients, see “What to tell patients.”

Cystoscopic detrusor injection

This procedure is usually done on an outpatient basis (eg, office, ambulatory surgery center). With the patient in the lithotomy position, 100 mL of 2% lidocaine is instilled into the bladder and is allowed 15 to 20 minutes to take effect. A flexible or rigid cystoscope can be used. Depending on the indication, the bladder is injected with 100 U to 300 U of botulinum toxin. The ideal depth of injection is 2 mm in the detrusor muscle, with each injection spaced about 1 cm apart. The recommended administration for 100 U is to inject 20 sites with 0.5 U per mL of saline and, for 200 U, to inject 30 sites with about 0.67 U per mL of saline.³⁸ The location of the injections into the detrusor can vary, as long as adequate spacing is assured.

Injection sites vary. Proponents of injecting the trigone argue that as it is an area of greater nerve density, patients will have a better clinical response. Opponents argue that trigonal injection could result in distal ureteral paralysis and subsequent ureteral reflux. However, this theoretical concern has not been observed clinically.

Urethral injection (off-label use)

The urethra can be injected cystoscopically or periurethrally. Cystoscopic injection involves localization of the external sphincter using the rigid cystoscope and collagen needle; a total of 100 U is injected into the sphincter under direct vision, typically at the 3 o’clock and 9 o’clock positions.³⁵ The periurethral technique is an option in women and involves a spinal needle with 100 U to 200 U of botulinum toxin injected into the external sphincter muscle at the 2 o’clock and 10 o’clock positions.

ADVERSE EFFECTS AND CONTRAINDICATIONS

Adverse effects are rare for urologic applications. The injections are localized, with little systemic absorption, and the doses are 1/1,000th of the theorized lethal dose in a 70-kg male.² The maximum recommended dose for a 3-month period is 360 U.

Generalized muscle weakness has been reported in a paraplegic patient and in a tetraplegic patient after detrusor injections.² Interestingly, both patients had return of bladder spasticity within 2 months, prompting speculation about diffusion of botulinum toxin through the bladder wall.²

Repeat injections can cause an immune response in up to 5% of patients.⁶ Patients undergoing repeat injections are at risk of forming neutralizing antibodies that can interfere with the efficacy of botulinum toxin.⁶ In a study by Schulte-Baukloh et al, all patients with antibodies to botulinum toxin had a history of recurrent urinary tract infection.³⁹

Botulinum toxin injection is contraindicated in patients with preexisting neuromuscular disease, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. It should also be avoided in patients who are breastfeeding, pregnant, or using agents that potentiate neuromuscular weakness, such as aminoglycosides.

Patients should be informed that some formulations of botulinum toxin include a stabilizer such as albumin derived from human blood, as this may be of religious or cultural significance.