Studies build evidence for botulinum toxin in OAB

Brisbane, Australia-Patients with neurogenic bladder overactivity treated with botulinum toxin A (Botox) have shown improvements in incontinence of up to 50% compared with placebo, but questions about the agent need to be addressed in further prospective, randomized trials before botulinum toxin can be accepted as an established treatment for voiding dysfunction, said Jeffrey Thavaseelan, MD, head of urology at the Royal Perth Hospital, Western Australia.

Dr. Thavaseelan described a randomized, double-blind, placebo-controlled study by Brigitte Schurch, MD, which investigated the safety and efficacy of botulinum toxin in 59 patients at eight centers (J Urol 2005; 174:196-200). Botulinum toxin doses of 200 and 300 units were used in a group of patients with neurogenic detrusor overactivity: 19 patients received 200 units, 19 received 300 units, and 21 received a placebo. Incontinence episodes, urodynamic parameters, and quality of life were studied, and follow-up was 6 months.

In addition to the incontinence improvement of 50%, maximum cystometric capacity improved by a mean of 150 mL in the botulinum toxin group and maximum detrusor pressure decreased by at least a mean of 50 cm of water compared with placebo.

In his own ongoing, double-blind, randomized, prospective trial of patients who received 200 and 300 units of botulinum toxin, preliminary data show that before the injections, the mean maximum detrusor pressure was 100 cm of water, which dropped to 15 cm of water after treatment. After 1 year, the mean detrusor pressure was 40 cm. Final results of the trial are expected by October 2006.

"There are a lot of questions that need to be answered," Dr. Thavaseelan said.

Botulinum toxin has not yet received approval from FDA for overactive bladder. Dosing protocol has not yet been established, including dilution levels, depth of the injection, and the optimal location for injecting, he said. The therapeutic effects of botulinum toxin last for 8 to 10 months, but reasons for its long duration compared with its duration in other muscles has yet to be clearly determined. Cost-effectiveness also needs to be addressed.

Dr. Thavaseelan presented a review of the literature on the use of botulinum toxin in urology, with most investigating neurogenic conditions. However, most of the evidence is still level 3.

There is no evidence in the literature of structural bladder changes in patients treated with botulinum toxin, but high doses can cause transient generalized muscle weakness, he said. Urinary retention is the most common side effect.

The agent's physiologic mechanism is unclear, but it seems to act on the afferent and efferent nerve pathways of the bladder. Its effect on the detrusor bladder muscle lasts 8 to 10 months, compared with 3 to 4 months on skeletal muscle. The effect of botulinum toxin in decreasing the symptoms of urgency and frequency suggests that the toxin may work through afferent pathways in the suburothelium, Dr. Thavaseelan said.

In a rat model, the injection of botulinum toxin into the prostate results in cellular apoptosis, and increasing dosages cause increasing cellular loss, he explained.

Clinically, if botulinum toxin were injected into the bladder, decreased bladder contractility, urgency, frequency, and bladder pain would be expected.

"It should have an effect in neurogenic overactivity, non-neurogenic overactivity, urgency/frequency syndrome, and in chronic pain," Dr. Thavaseelan said.

Fourteen papers covering 300 patients with non-neurogenic activity injected with botulinum toxin have been published with level 3 evidence.

The largest of these trials was carried out by Daniel M. Schmid, Jr, MD, and his colleagues and was presented at the 2005 AUA annual meeting (J Urol 2005; 173:149, abstract 547). The results showed an 88% improvement in 100 patients injected with botulinum toxin, and 80% of the subjects remained dry at 1 to 2 weeks. The mean duration of botulinum toxin's effectiveness was 9 months.

A total of 20 published studies have examined the use of botulinum toxin in neurogenic overactivity. A multicenter, prospective study by André Reitz, MD with 200 patients, is the largest of these trials (Eur Urol 2004; 45:510-5). The results showed a 50% improvement in maximum cystometric capacity and mean voiding pressure, Dr. Thavaseelan said.

Dr. Thavaseelan is a member of the Allergan advisory board.