Urethral and Bladder Injections for Incontinence Including Botox

Stress urinary incontinence (SUI) and urge incontinence (UI) are increasingly significant health concerns for millions of women. Investigation continues into the use of different types of procedures for the surgical management of UI that can be done in the ambulatory office without the use of general or regional anesthesia. Injectable treatment for SUI and UI lend themselves to the ambulatory or office setting and mimic the efficacy and safety profiles of currently available procedures.

Stress urinary incontinence (SUI) and urge incontinence (UI) are increasingly significant health concerns for millions of women. Approximately 180,000 surgical procedures are performed for genuine SUI alone. The lack of a single, reproducible, permanent, and minimal-risk procedure has led to the development of several minimally invasive options that provide the hope of reasonable efficacy and minimal morbidity. Reimbursement trends have placed an emphasis on interventions that require minimal hospitalization or that can be performed in the ambulatory office without the use of general or regional anesthesia and attendant recuperative facilities.

Injection therapy has been used sparingly for the management of SUI for nearly 2 decades, but has been limited by durability and antigenicity issues associated with bovine collagen. Food and Drug Administration (FDA) approval of carbon particulate technology (Durasphere) has provided another option for bulking, but this treatment is limited by difficulty with injection (because carrier extrusion can result in injection-needle obstruction). Because of these concerns, many physicians would use Durasphere only in the controlled setting of the operative suite, detracting from the financial benefit associated with in-office bulking therapy. This issue was addressed by the manufacturer, and an improved formulation (Durasphere EXP) was introduced after FDA approval was given in October 2003; injection of this treatment is as easy as injection of collagen. The use of bulking therapy had been less than optimal; however, the advent of several new bulking agents (each with unique tissue-interaction characteristics, the promise of greater durability, fewer injection sessions, and no antigenicity) promises to alter the role of bulking therapy in the overall management schema for SUI. Selection of patients seems to be crucial to the outcome of the intraurethral injection of bulking agents. The ideal candidate for this procedure has good anatomic support; a compliant, stable bladder; and a malfunctioning urethra as evidenced by a low leak point pressure. Other patients who may benefit from the procedure are patients with high leak point pressure and minimal hypermobility and elderly women with bladder base mobility who are less active and are a poor surgical risk for other interventions.

Investigation continues into the use of different types of procedures for the surgical management of UI. These procedures lend themselves to the ambulatory or office setting and mimic the efficacy and safety profiles of currently available procedures (such as sacral nerve neuromodulation).

Injectable agents for treating SUI

The successful use of periurethral bulking agents is dependent on several factors, such as the composition of the material, the facility of agent use (ease of preparation and implantation), and a receptive host environment (optimized hormonal environment, integrity of urethral anatomic components, intact periurethral fascia). Three categories of materials have been investigated for periurethral bulking: human (autologous or allograft), xenograft, and synthetic.

The optimal attributes for bulking materials are biocompatibility, minimal or no immunogenicity (hypoallergenic), and integrity of the material formulation (there should be little or no separation of agent subcomponents [carrier and particulate solid]). Rheologic (deformation within tissue) characteristics of the agent should be affected positively by adequate material viscosity, surface tension, and tissue response (wound healing). These attributes for any specific agent should be reproducible. Tissue-response characteristics should demonstrate minimal fibrotic ingrowth and little extracapsular inflammatory response (if encapsulation occurs). Agent volume after injection should be retained with minimal resorption. The most ideal scenario for any soft tissue-bulking agent is a single injection with permanent tissue residence of the agent (and partial or total incorporation into the host tissues); however, available agents do not ideally fulfill these criteria because of isolated or combined agent and host factors (eg, lack of resorption, agent admixture separation).

The goal of endoscopic injection therapy for SUI is to provide a minimally invasive, effective, and safe alternative to open surgery. Although the technique has been available for decades, the ideal injectable material has yet to be developed. In addition to being biocompatible, nonantigenic, noninfectious, and noncarcinogenic, the material must demonstrate anatomic integrity. This requirement implies that the material conserves its volume over time. Although bovine collagen is safe for use as injection treatment for SUI, it lacks this anatomic integrity. This fact reduces the ability of collagen to be cost effective. A significant volume is required at each injection session, and multiple injection sessions are the rule, reducing cost effectiveness and resulting in patient inconvenience and patient dissatisfaction with collagen or injectable therapy in general. Information on collagen has been well documented.

Treatment with Durasphere pyrolytic carbon-coated zirconium oxide beads was approved by the FDA in 1999. The beads are suspended in a water-soluble β-glucan vehicle. The randomized, multicenter, double-blind study that was accepted by the FDA showed that collagen and Durasphere had similar outcomes and that the original Durasphere had a slight benefit. Durasphere is more viscous than collagen, and as mentioned earlier, its injection was more technically demanding than that with collagen (although injection has become easier with the introduction of Durasphere-EXP). Renewed concern has been expressed about material migration after injection. Microcrystalline components of the bulking agent should be composed of uniform spheroidal particles sized greater than 80 μm (the approximate size required to avoid migration as determined in studies involving polytetrafluorethylene [Teflon]). Migration is influenced by the ability of host macrophages to phagocytize particles, and smaller particle sizes have been shown to migrate to distant locations with Teflon injection. Direct embolization of material is caused by high-pressure injection, resulting in material displacement into vascular or lymphatic spaces. Injection technique should rely on larger-sized particles that are administered with low-pressure injection instrumentation. This requirement should not be a problem with Durasphere-EXP, as its particles range in size from 95 to 200 μm, whereas the particles in the original Durasphere are significantly smaller (200–550 μm); however, the Durasphere-EXP’s smallest particles are still greater in size than the 80 μm needed for safety.

Agents in Development

Synthetic calcium hydoxylapatite is identical to the material found in human teeth and bones. The agent is composed of hydroxylapatite spheres (which are uniform in shape, smooth, and 75–125 μm in size) in an aqueous gel composed of sodium carboxylmethylcellulose (Coaptite). Plain film radiography or ultrasonography may be used localize this material and can be useful adjuncts to assessing implantation. The first FDA-approved indication for this material has been obtained, specifically for soft tissue marking as an adjunct to radiographic focusing for radiotherapeutics. Agent injection is performed with a small bore (21-gauge needle) and standard cystoscopic instruments. An ongoing, large-scale North American pivotal trial is accruing more than 250 women. Twenty-one women have received Coaptite, 18 women received collagen, and the subjects have been followed for 1 year since last injection. The average number of injections was 2.0 for Coaptite and 2.3 for collagen. The total volume injected was 3.7 mL for Coaptite and 7.4 mL for collagen. Eighty-six percent of Coaptite recipients improved by at least one Stamey grade, 67% improved by two grades, and 38% were completely continent, whereas among collagen recipients, the respective percentages were 66%, 55%, and 44%. Overall pad weight reduction in a 1-hour stress pad test was at least 75% in 77% of Coaptite recipients but in only 55% of collagen recipients; reduction of 90% or greater occurred in 46% of Coaptite recipients and 33% of collagen recipients. No prolonged retention, urgency, or periurethral erosion or abscess was seen in either group. This agent has similar injection characteristics to collagen and seems to require a lower injected volume for a somewhat more durable effect.

Another biologic agent, Zuidex, consists of dextranomer microspheres in a cross-linked hyaluronic acid (HA) vehicle. HA is a water-insoluble, complex glycosaminoglycan that is composed of disaccharide units, which form molecules of 23 million molecular weight, and is dissolved in normal saline for urethral bulking purposes. This composite gel has significant elasticity and high viscosity. These biologic characteristics have led to the use of hylan gels for soft tissue bulking purposes. It is completely biodegradable and nonimmunogenic. HA functions as the transport compound and is resorbed within 2 weeks after injection. The dextranomer microspheres function as the bulking agent, are 80 to 200 μm in size, do not show fragility with insertion, and remain in the injection site for about 4 years. Injection is performed using standard cystoscopic equipment with minimal injection pressure. An ongoing clinical trial in the United States is evaluating this agent for treating SUI. The technique for HA injection does not require endoscopy. A small device is placed into the urethra, and the needles direct the injected material in 1-mL aliquots at the midurethra. Substantive data have shown the efficacy and safety of this agent, allowing FDA approval for use in treating vesicoureteral reflux and pediatric incontinence. The site for incontinence injections is the bladder neck, as had been the convention for the treatment of SUI until this new trial of HA in women with SUI.

Results of dextranomer injection for pediatric incontinence showed no associated adverse events and substantial improvement 12 months after injection. Sixteen patients (with a variety of underlying causes for their incontinence) underwent a mean of 2.3 injections (mean volume, 2.8 mL) and subsequent annual follow-up. According to 1-hour pad tests and diary data, 75% of patients improved at 6 months, and 50% improved at 12 months. Follow-up at 2 years indicated relative stability of incontinence parameters, as compared with 1-year data. No local injection-site complications or immunologic sequelae resulted. Similar durability and safety findings have been identified with this material when used for the reflux indication.

Synthetic agents pose a potential benefit as bulking agents because of their stability (nonbiodegradability). Silicone is a hydrogel suspension that has polyvinylpyrrolidone (povidone) as the carrier (which also acts as a lubricant for the injection system) and solid polydimethylsiloxane elastomer (vulcanized silicone) as the bulking agent. The elastomer is a particulate of varying shapes and conformal configurations. Particle size is markedly variable; 25% of particles are less than 50 μm in size, and some particles are greater than 400 μm in size. Silicone delivery requires high-pressure administration, but with newer equipment allows easier delivery of this material. Although the use of silicone is well established in Europe, concerns regarding silicone stimulation of the immunologic response have limited evaluation of this agent in the United States. A clinical trial evaluating the use of Macroplastique (a type of silicone) as a bulking agent is in progress in North America. A Scandinavian report followed 22 women for 2 years after receiving a silicone injection. Subjective and objective criteria showed stability and persistent benefit. Overall pad test data showed dramatic reduction (mean pretreatment level, 147 g; mean post-treatment level, 9 g). No long-term local or systemic complications were noted.

Ethylene vinyl alcohol copolymer suspended in dimethyl sulfoxide or Uryx solution is being evaluated as an embolic agent and a bulking agent. On injection and exposure to solution (blood or extracellular space) at physiologic temperatures, the dimethyl sulfoxide diffuses from the co-polymer and causes the ethylene vinyl alcohol to precipitate into a complex spongiform mass. This phase change requires diligent separation of the agent and body-temperature fluids until implantation occurs. Early experience with this agent suggested that optimal results can be obtained with injection in a slightly more distal urethral location within the urethra (approximately 1.5 cm distal to the bladder neck); with a slower rate of injection (at least 30 s/mL/injection site); and without the need to observe visual coaptation at the completion of injection, as the volume injected is limited to 2.5 mL on each side of the urethra. Using these end-point criteria, results have been good. With this material, injection is done with this set volume rather than with an end point of coaptation of the urethra or bladder neck at the time of injection. A large-scale North American trial is in progress. The trial incorporated 237 women with genuine SUI and used a prospective, randomized (Uryx-to-bovine collagen ratio, 2:1) schema. Treated patients were for 1 year after last injection. At 6 months, 40 Uryx recipients and 23 collagen recipients have been evaluated (at 12 months, 21 and 13 subjects, respectively, had been evaluated). The mean total volume of material required for injection was lower for Uryx (4.4 mL) than for collagen (6.9 mL). At 6 months, 63% of Uryx recipients are dry (no incontinent episodes), compared with 48% of collagen recipients. At 12 months, 74% of Uryx recipients were dry, compared with 40% of collagen recipients. Rates of postimplantation urgency and dysuria were similar between the two arms. This result suggests that, unlike collagen, Uryx maintains a durability of response that has not been noted with biologic agents and may be the first synthetic material to do this without substantive complication issues.

A requirement for FDA trials with these agents is active comparison with bovine collagen. No head-to-head data exist between these evolving agents for treating genuine SUI; however, one trial has compared Macroplastique with dextranomer and HA for the treatment of ureteral reflux in children.

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