The first in its class, and the first new class of medications for the treatment of OAB in over 30 years, mirabegron, a β3-agonist, was FDA approved for overactive bladder in June 2012. In contrast to antimuscarinics, this class of drugs targets the β3 receptors in the bladder dome that promote detrusor relaxation. It represents an exciting alternative to the antimuscarinics that have had poor continuity rates of only 25–50 % at 1 year, secondary to side effects [12].

Four phase III trials with mirabegron have demonstrated efficacy and safety [12, 20–22].^. These studies included comparisons to placebo in three of the four as well as to tolterodine in two of the four studies. Regarding efficacy among these studies, mirabegron was superior to placebo and similar to tolterodine. Regarding side effects, mirabegron was better tolerated with lower rates of dry mouth compared to tolterodine (2.3–2.8 % vs. 8.6 %) [20]. Specifically, among 1,329 patients randomized to mirabegron 50 mg, 100 mg, or placebo, decreases in incontinence episodes were −1.47 (±0.11), −1.63 (±0.12) and −1.13 (±0.11) respectively. Similarly, the decrease in voids between active and placebo arms was −1.66 (±0.13), −1.75 (±0.12), and −1.05 (±0.13). Both findings were statistically significant [12]. In another randomized, double-blind study, doses of 25 and 50 mg were compared to placebo. Among these 1,306 patients randomized, mean incontinence episodes and number of micturitions were both significantly reduced in the mirabegron groups. The 50 mg dose, but not the 25 mg, also significantly increased the mean-voided volume over placebo [22] (for additional details see Table 6.2).

The safety and tolerability profile of mirabegron has been excellent. Some small, but clinically insignificant increases in pulse rate (0.8–0.9 bpm) and blood pressure (1.5 mmHg SBP and 1.0 mmHg DBP) have been noted [22]. Still, rates of hypertension in another study in both 50 and 100 mg mirabegron dose group were actually lower than placebo [21] . No studies demonstrated significant increases in cardiac events [12, 20–22]. The main consideration for an alternate drug recommendation remains uncontrolled hypertension (blood pressures >180/110). Still, while blood pressure monitoring is indicated, again, the actual clinical impact has not typically been significant.

Onabotulinum Toxin-A (BTX-A), a serotype of the neurotoxin produced by Clostridium botulinum, is increasingly utilized as a safe and effective treatment option for refractory overactive bladder. Proof of concept of BTX-A use in the lower urinary tract stems from neurogenic bladder literature and has expanded its use into nonneurogenic cases [23].

BTX-A blocks acetylcholine release at the presynaptic neuromuscular junctions, decreasing detrusor overactivity and incontinence. It is additionally believed to alter urothelial sensory afferent pathways and help alleviate hypersensitivity responses, an explanation as why BTX-A is also effective in decreasing urinary urgency and frequency and increasing bladder capacity [23, 24].

Efficacy and safety of BTX-A have been demonstrated in multiple studies [25–30]. Efficacy typically defined as >50 % reduction in symptoms ranges at 60–80 %, with continence seen in approximately 22 % [24, 28, 29]. Doses of 200 or 300 units are often used in neurogenic cases. However, the literature in nonneurogenic overactive bladder points to an optimal risk/benefit dose of 100 units [27]. Higher doses have been associated with higher rates of retention and need for catheterization, and in one study with 200 units used in 28 women, this rate was as high as 43 % [31].

A recent, larger randomized trial of 242 women directly compared antimuscarinic therapy with intravesical BTX-A in the ABC trial: Anticholinergic versus Botulinum Toxin-A Comparison Trial for the Treatment of Bothersome Urge Urinary Incontinence [26]. Refractory patients with idiopathic overactive bladder were randomized to antimuscarinic therapy plus a saline intravesical injection vs. 100 units BTX-A plus a placebo pill. At 6 months, those receiving BTX-A were more likely to be continent: 27 % vs. 13 % (p = 0.003), with otherwise similar decreases in the number of incontinence episodes daily (initially a baseline of 5 decreased by 3.4 and 3.3/day). Expectantly, urinary tract infection rates (33 %) and intermittent self-catheterization at 2 months (5 %) were both higher in the BTX-A group. However, symptom control at 6 months was also significantly higher in the BTX-A group [26].In a recent cost analysis, the cost comparison was similar between the two treatments over the first 6 months, however, after that time (assuming average efficacy of BTX-A being 9 months), the cost profile favors BTX-A [32].

With BTX-A use, important contraindications/considerations remain: current urinary tract infection, malignancy, obstruction, pregnancy, and neuromuscular junction disorders such as myasthenia gravis (auto-antibodies to acetylcholine receptors) and Lambert–Eaton Syndrome (failure of nerves to release acetylcholine).

InterStim is a form of sacral nerve neuromodulation that is currently FDA approved for: urgency/frequency, urgency incontinence, nonobstructive urinary retention and fecal incontinence. It consists of a lead wire with four electrodes that are positioned along the sacral nerve roots—most commonly S3. This is then attached to an implantable pulse generator (IPG) that is surgically placed in the upper buttocks and provides a nonpainful electrical stimulation. Procedurally, this involves a two-step process (either in office percutaneous nerve evaluation (PNE) or stage I in the operating room) where the patient is able to test the efficacy (reduction in symptoms >50 %) prior to final IPG placement. Proof of concept for InterStim was devised in animal models by Tanagho and Schmidt in the 1970s, and it has been FDA approved in the United States for bladder indications since 1997 [33].

Several advances have been introduced including: a tined lead that has decreased invasiveness of the procedure, and a smaller IPG battery that has improved comfort. Evidence regarding how the tined lead is placed has also resulted in procedural improvements. Use of the curved vs. straight stylet in a randomized crossover trial demonstrated a clear intraoperative superiority with the use of the curved stylet [34]. Furthermore, the safety profile of InterStim, in light of these advances, is excellent. Major complications and morbidity have been uncommon, and estimates of infection (previously up to 10 %) have been closer to 3 % and of chronic pain (previously up to 16 %) have been closer to 8 % in more recent studies [35–41].

Theories on how InterStim works include modulation of the somatic afferents in the pudendal nerves which could both aid inhibitory mechanisms or revive an ability to void by relieving abnormal guarding reflexes—both of which would normalize voiding function [42, 43]. Additionally, recent work has demonstrated that InterStim modulates learning center regions of the CNS [42]. Still, a precise understanding of how InterStim functions remains unclear.

The efficacy of sacral nerve neuromodulation is well supported in multiple clinical trials. The literature demonstrates success for urgency/frequency and urgency incontinence to range between 56 and 68 % (up to 80 %). Efficacy in patients with urinary retention is approximately 70 %, and in fecal incontinence approximately 85 % [35, 36, 44–47]. Success is being defined as 50 % or greater reduction in symptoms.

The recent InSite Trial compared InterStim directly to standard medical therapy (antimuscarinic medications) [48]. In 147 patients with an overactive bladder randomized to these modalities, those receiving InterStim had significantly higher-efficacy rates: 61 % vs. 42 % (p < 0.05). Quality of life measures were also significantly improved with InterStim compared to medications. 86 % of InterStim subjects compared to 44 % of those undergoing standard medical therapy reported “improved” or “greatly improved” urinary symptoms (p < 0.001) [48].