Mechanism of Action

Parasympathetic muscarinic receptor activation of the detrusor muscle results in bladder voiding, while the maintenance of continence and normal bladder function is under a complex modulation that includes a cholinergic component involving muscarinic receptors [ ]. Although initial preclinical studies suggested that anticholinergics act by reducing the contractility of the detrusor muscle, evidence suggests that their mechanism of action is associated with sensory pathways [ ]. Five muscarinic receptors exist in humans, all of which (M ₁ –M ₅ ) are expressed within the bladder [ ], although the M ₂ and M ₃ subtypes are present in a greater proportion. However, as muscarinic receptors are located in other regions of the body, including salivary glands, gastrointestinal smooth muscle, and iris sphincter muscles, their blockade is associated with other side effects, which include dry mouth, constipation, and visual disturbance.

Each antimuscarinic demonstrates a different binding affinity for each of the muscarinic receptor subtypes [ ] and their pharmacokinetic properties, as such, there is a variation in the side-effect profile between them. It is unsurprising therefore that discontinuation rates due to poor tolerability are high [ ], with discontinuation rates in clinical trials as high as 31% at 12 weeks [ ], with much poorer persistence rates demonstrated beyond 12 months [ ]. Younger patients are more likely to discontinue antimuscarinic therapy than the elderly, and it is dry mouth, the most frequently reported side effect [ ] that is commonly reported as the reason behind discontinuation [ ].

Efficacy

Several large-scale randomized placebo-controlled trials have assessed the efficacy of antimuscarinic monotherapy, versus tamsulosin monotherapy and combination therapy. Kaplan [ ] reported the outcomes of over 800 patients over 40 years old, who had an IPSS > 11, and storage LUTS randomized to receive either tamsulosin 400 mcg monotherapy, tolterodine ER 4 mg monotherapy, their combination, or placebo. After 3 months of treatment, 80%, 70%, 65%, and 62% of patients randomized to either combination therapy, tamsulosin, tolterodine, or placebo, respectively, reported benefit. Furthermore, combination therapy was significantly more effective than either tamsulosin or tolterodine monotherapy at reducing total number of daily micturitions, urgency episodes, total IPSS, and the IPSS quality of life index.

Further data on antimuscarinic therapy is taken from the phase II SATURN study [ ], which recruited over 900 men with both storage and voiding LUTS. Patients were randomized to receive either tamsulosin 400 mcg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6, or 9 mg and tamsulosin; or placebo. After 12 weeks, combination therapy was associated with significant improvements in micturition frequency, voided volume, and urgency episodes than tamsulosin monotherapy, while there was no significant improvement in total IPSS, which was the primary endpoint of the study. The outcomes of the NEPTUNE placebo-controlled study and the open label extension, NEPTUNE II [ ], however do demonstrate significant improvements in the total IPSS, including significant reductions in both the storage and voiding components. Furthermore, solifenacin and tamsulosin combination therapy was associated with significant improvements in micturition frequency, urinary urgency episodes, voided volume and Q _max , findings that were maintained over the 52-week open label extension of either solifenacin 6 mg + tamsulosin 400 mcg and solifenacin 9 mg + tamsulosin 400 mcg.

From a pragmatic perspective, several placebo-controlled trials have evaluated the efficacy of antimuscarinics as add on therapy to tamsulosin in male patients with refractory LUTS. Chapple et al. [ ] reported the outcomes of 652 men over the age of 40 who described refractory storage LUTS while taking a stable dose of tamsulosin. Patients were randomized to a 12-week add on therapy to tamsulosin with either tolterodine ER 4 mg or placebo. Improvements using the patient perception of bladder condition (PPBC) were reported by 63.6% of men randomized to the tolterodine arm, as compared to 61.6% in the placebo arm ( P = .66). Patients receiving tolterodine compared with placebo also demonstrated significant improvements in 24-h micturitions (− 1.8 vs. − 1.2; P = .0079), 24-h urgency episodes (− 2.9 vs. − 1.8; P = .001) in addition to reductions in the IPSS storage subscore (− 2.6 vs. − 2.1; P = .03) compared to placebo. Similar findings have been demonstrated for solifenacin in the context of the VICTOR (VESIcare In Combination with Tamsulosin in OAB Residual symptoms) trial [ ]. A total of 397 patients with refractory storage LUTS (≥ 8 micturitions and ≥ 1 urgency episodes per day) on tamsulosin monotherapy were recruited to this 12-week placebo-controlled trial. While solifenacin add on therapy did not significantly affect the mean number of micturitions (− 1.05 vs. − 0.67; P = .135) as compared with placebo, it was associated with significantly fewer daily urgency episodes (− 2.18 vs. − 1.1; P < .001). Patient reported outcome measures demonstrated no significant differences between the two groups.

Adverse Events

The NEPTUNE II follow-on study demonstrates the adverse event profiles of solifenacin over a year-long follow-up period. Of the 1066 patients receiving treatment in NEPTUNE II, 499 patients (46.8%) experienced treatment-emergent adverse events (TEAEs), the majority of which were mild to moderate in severity. The most commonly reported adverse events were dry mouth (12.4%), constipation (5.2%), dyspepsia (2.7%), hypertension (2.4%), urinary tract infection (2.3%), and nasopharyngitis (1%). The meta-analysis by Chapple et al. [ ] confirms that dry mouth is the most commonly reported adverse event, at 30% and 8% in treatment and placebo arms, respectively, followed by pruritus (15% and 5%).

Despite this, only 28 patients (2.6%) discontinued treatment in the NEPTUNE study. In NEPTUNE and NEPTUNE II, the median PVR increased from 26 mLs at baseline (0–150 mLs) to 32 mLs (0–346 mLs) at treatment end. Sixty-eight patients (6.4%) developed a postvoiding residual (PVR) in excess of 150 mLs at various points during the study, including 4 patients with a PVR ≥ 300 mLs. In total, 13 out of 1208 patients (1.1%) included in either NEPTUNE or NEPTUNE II developed urinary retention, 8 of whom had AUR. The median duration of treatment preceding the onset of urinary retention was 77 days (6–347 days).

The development of urinary retention is considered to be the greatest concern for treatment with any pharmacotherapeutic agent directed at LUTS in men. The majority of studies assessing the rate of urinary retention involve short-term data (over 12 weeks) and men with large PVRs (usually in excess of 200 mLs) or poorer flow rates (usually less than 10 mLs/s)