Dr. MacDiarmid is Associate Professor, Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC. He serves as an advisor to Ortho-McNeil Pharmaceuticals and Watson Pharmaceuticals.

Scott MacDiarmid, MD

	The primary treatment of overactive bladder (OAB) is behavioral modification and medication with the goal of relieving symptoms and balancing drug treatment efficacy with side effects and costs. Unfortunately, many patients do not reach their treatment goal with conservative therapy and suffer from a new disease that in day-to-day practice is seldom talked about by patients and health care providers. This disease is called “refractory OAB,” or what I have termed “ROAB.” 

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	This article provides a real-world definition of ROAB and its prevalence, then examines treatment options, with a focus on percutaneous tibial nerve stimulation as a noninvasive form of neuromodulation “for the masses.”

	How many patients have ROAB? Simply stated, millions do! In fact, ROAB is much more prevalent than OAB that is currently effectively managed by medical therapy. Let’s face it, more than 50% of OAB patients who are treated for their condition do not respond favorably to or reach their treatment goal with medication 

	A 2012 AUA/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU) guideline panel defines the refractory OAB patient as one who has failed appropriate behavioral therapy of sufficient length and a trial of at least one antimuscarinic medication administered for 6 to 12 weeks 

	A more real-world definition of ROAB includes those patients who:

		do not respond to medication in spite of trying multiple agents

		have a contraindication to taking medication

	Patients with ROAB are those who keep coming back after cycling through various agents and are still symptomatic. They are those who do not respond to their 2 weeks of samples and who simply give up, thinking they cannot be helped and unfortunately surrender to their condition. In addition, think about the millions of men and women with OAB symptoms who are only partially satisfied with their antimuscarinic agent, alpha-blocker, or beta-3 agonist and who would jump at the chance of achieving better symptom relief by adding a noninvasive treatment to their current medical therapy.

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	Unfortunately, we have a significant clinical problem when it comes to the treatment of ROAB, which is that we are dramatically undertreating it.

	Sacral nerve stimulation (InterStim), percutaneous tibial nerve stimulation (PTNS [Urgent PC]), and onabotulinumtoxinA (Botox) are excellent treatment options for ROAB, but I believe that they are dramatically underutilized. For instance, there have been approximately 150,000 sacral nerve stimulators placed worldwide since 1997, with 25,000 implanted in the United States in 2012. In the same year, approximately 15,000 and 35,000 patients were treated with PTNS and onbotulinumtoxin, respectively, according to data on file from the manufacturers of these products. Estimating that there are 10,000 urologists and urogynecologists in the U.S., we are each treating on average seven or eight ROAB patients annually. Clearly, we need to do better.

	In spite of the effectiveness of sacral nerve stimulation, many urologists do not perform an InterStim procedure and don’t refer patients to those who do. Some perceive it as too invasive or expensive, especially in elderly patients and in those who are frail or have a number of medical comorbidities. Onbotulinumtoxin injected directly into the detrusor muscle endoscopically is an excellent neuromodulation treatment for refractory OAB, but its use in clinical practice is somewhat limited because of the risk of retention associated with the treatment.

	Clearly we need additional and less-invasive therapies.

	Percutaneous tibial nerve stimulation offers patients an in-office, noninvasive treatment alternative, and I believe it is neuromodulation for the masses: the masses of physicians who are not liberally performing neuromodulation therapies and the masses of untreated ROAB patients, including the frail and elderly.

	PTNS is a minimally invasive neuromodulation system designed to deliver retrograde electrical stimulation to the sacral nerve plexus through percutaneous electrical stimulation of the posterior tibial nerve (figure 1). Using a battery-powered, hand-held stimulator and a 34-gauge needle electrode, the tibial nerve is accessed and stimulated. Patients receive a 30-minute weekly treatment in the office for 12 weeks. Treatment responders require additional therapy at individually defined treatment intervals for sustained relief of OAB symptoms.

	The literature clearly supports the efficacy of PTNS in the treatment of OAB. The Overactive Bladder Innovative Therapy (OrBIT) trial was a randomized, multicenter, controlled study that compared the effectiveness of PTNS to extended-release tolterodine (Detrol LA) in 100 patients with OAB 

 The global response assessment demonstrated that subject assessment of OAB symptoms compared to baseline was statistically significant in the PTNS arm, with 79.5% reporting cure or improvement compared to 54.8% of subjects on tolterodine (

<.01). After 12 weeks of therapy, objective measures improved similarly in both groups for reductions in urinary frequency, urge urinary incontinence episodes, urge severity and nighttime voids, as well as for improvement in voided volume.

	The Study of Urgent PC vs. Sham Effectiveness in the Treatment of Overactive Bladder Symptoms (SUmiT) was a multicenter, double-blind, randomized, controlled trial comparing the efficacy of PTNS to sham through 12 weeks of therapy 

 In the study, 220 adults were randomized 1:1 to 12 weeks of treatment with weekly PTNS or sham therapy. The 13-week subject global response assessment for overall bladder symptoms demonstrated that PTNS subjects achieved statistically significant improvement in bladder symptoms, with 54.5% reporting moderately or markedly improved responses from baseline compared to 20.9% of sham subjects (

	Voiding diary parameters after 12 weeks of therapy showed PTNS subjects had statistically significant improvements in frequency, nighttime voids, voids with moderate to severe urgency, and urinary urge incontinence episodes compared to sham. The level I evidence provided by this pivotal study demonstrated that PTNS is a safe and effective therapy in treating OAB symptoms.

	Peters et al followed 50 participants from the SUmiT trial who met the primary effectiveness endpoint after 12 weekly PTNS treatments 

 Patients were prescribed a fixed-schedule, 14-week tapering protocol followed by a personal treatment plan aimed at sustaining OAB symptom improvement. Of this group, 29 patients completed the 36-month protocol and received a median of 1.1 treatments per month. At 3 years, 77% maintained moderate or marked improvement in OAB symptoms.

	Compared to baseline, median voids per day decreased from 12.0 to 8.7, and urge incontinence episodes per day decreased from 3.3 to 0.3. All quality of life parameters remained markedly improved from baseline through 3 years. Based on multiple studies, the revised AUA/SUFU guideline for the treatment of OAB classify PTNS as a recommended third-line treatment (evidence strength grade: C) 

www.auanet.org/education/guidelines/overactive-bladder.cfm

	Having witnessed the benefit of PTNS in hundreds of ROAB patients, I have slowly expanded its usage to the following groups:

		patients with neurogenic bladder and who are voiders with OAB symptoms

		those with mixed urinary incontinence with predominant OAB

		difficult populations with OAB, including those with radiation cystitis and pelvic pain syndrome

		patients with nighttime frequency with OAB

		partial responders and those with milder OAB symptoms.

Next - Maximizing therapy: Treatment algorithm

	In order to maximize efficacy and help millions of OAB patients, we should embrace and liberally offer them all three neuromodulation therapies. In order to do so, I recommend the adoption of an OAB treatment algorithm in order to drive efficacy. Figure 2 shows my treatment algorithm for these patients.

	Most patients are initially treated with a combination of antimuscarinic agents and behavioral therapy. Nearly all patients are started on behavioral treatments, including fluid modifications, bladder retraining, and pelvic floor rehabilitation. Many are offered to see our in-house team of physical therapists, who are experts in treating patients with voiding dysfunction.

When patients fail two antimuscarinics, they are offered mirabegron (Myrbetriq). We have had tremendous success treating ROAB with the beta-3 agonist either as monotherapy or in combination with antimuscarinics. In patients with milder symptoms, I tend to switch to mirabegron, and in the more severe partial responding population, I often add it to the antimuscarinic. The efficacy and tolerability of mirabegron has been such that I now often use it first line prior to starting antimuscarinics.

	When medical and behavioral therapy does not reach the patient’s treatment goal, I offer nearly all ROAB patients neuromodulation. Each of the three therapies have their inherent advantages and disadvantages, and I believe it should be up to patients-not me-to choose which one best suits them. Utilizing a commonsense approach, many elderly patients and those with multiple comorbidities are only offered PTNS.

	Of course, ROAB patients who have not exhausted all of the available antimuscarinics have the option of trying a third or fourth medication, and in some cases this may be beneficial.

	Patients who decline neuromodulation and have exhausted all pharmaceuticals, unfortunately, have reached the end of the treatment algorithm. Those who fail a neuromodulation therapy are usually re-offered the other two options, depending on patient factors. In addition, many partial responders to neuromodulation are restarted on an OAB agent that has provided some prior benefit to help augment their therapy.

	PTNS offers patients with refractory OAB or “ROAB” a minimally invasive, office-based procedure that is safe, effective, and an important addition to our therapeutic armamentarium. Utilizing a treatment algorithm and adopting a mindset of treating patients beyond medication is integral in driving excellence and maximizing therapeutic outcomes for our patients with refractory OAB.

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Articles

This article provides a real-world definition of refractory overactive bladder and its prevalence, then examines treatment options, with a focus on percutaneous tibial nerve stimulation as a noninvasive form of neuromodulation “for the masses.”

Scott MacDiarmid, MD

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