Authors: John C. P. Piedad, Mazen Allam, Wasim Mahmalji
Categories: Review, Pharmacotherapy, Stent symptoms, Ureteric stent
Source: Bladder
Authors: John C. P. Piedad, Mazen Allam, Wasim Mahmalji
Ureteric stenting is a ubiquitous procedure, but it is associated with symptoms that affect psychological well-being and quality of life. While many factors are linked to worse symptomatology, some innovative modifications to the stent’s structure, as well as treatments, have been studied to reduce their clinical impact. Pharmacotherapy is a well-evaluated treatment modality derived from the treatment of lower urinary tract symptoms not related to stents.
This review focuses on these pharmacological treatments. Several drug classes have been trialed to treat stent-related symptoms. Most of these studies investigated adrenoceptor modulators (both alpha-blockers and beta-3 agonists), muscarinic receptor antagonists, phosphodiesterase-5 inhibitors, as well as novel pharmacological modalities. Most trials and subsequent meta-analyses support treatment over placebo and controls, and some drugs are better at treating certain symptom domains, such as phosphodiesterase-5 inhibitors working on sexual issues. Furthermore, a combination therapy with alpha-blockers and muscarinic receptor antagonists appears to be superior to monotherapy with either of them. Treatments are also well tolerated.
However, initiating pharmacotherapy should be part of a shared decision-making approach that balances the severity of symptoms and the duration the stents will remain in situ against potential side effects.
Ureteric stents are essential in maintaining ureteric patency in obstruction or following procedures of the upper urinary tract. However, stent-related symptoms (SRS), namely, lower urinary tract symptoms (LUTSs), hematuria, and loin pain are associated with impairments to psychological health and quality of life (QoL) [1]. Several factors contribute to worse symptomatology. Stent length and crossing the midline [2,3], as well as wider stent diameter, are linked to worse SRS [4]. Non-silicone polymer and “harder” stents elicit worse SRS compared to thier silicone (“soft”) counterparts [5]. Different treatments have been considered, such as drug-eluting stents, for example, with the antimicrobial triclosan [6]. Their clinical utility beyond maintaining ureteric patency, however, remains to be seen. Another innovative solution is a suture stent, which has improved SRS compared to conventional stents, where a proximal coil bypasses the obstruction. The bladder contains only sutures to facilitate removal, which means there is no distal stent coil irritating the bladder [7]. Periureteric botulinum toxin A injection was associated with improvements in stent-related pain, but not LUTSs [8]. A comparison of intravesical oxybutynin, alkalinized lidocaine, or ketorolac versus saline solution (placebo) found that ketorolac, a non-steroidal anti-inflammatory, was associated with improvements in SRS compared to other solutions [9]. Intravesical glycosaminoglycans (GAGs) also elicited similar improvements in SRS in one trial [10]. Pharmacotherapy for SRS has been extensively investigated for its clinical utility, revealing several options that are translated from its use in the treatment of non-stent-related LUTS. This review examines the literature on the pharmacological treatment options for SRS.
Modulation of adrenergic receptors has been used in the treatment of LUTS due to their ubiquitous expression in the smooth muscle of the ureters down to the lower urinary tract [11], and thus, has been used to treat SRS. Alpha-1 receptors mediate bladder neck and urethral contraction, and thus, their blockade reduces urinary tract smooth muscle tone. These include tamsulosin, alfuzosin, doxazosin, terazosin, silodosin, and naftopidil, among others (Table 1).
Three trials, two of which were placebo-controlled [12,13], evaluated the effect of tamsulosin monotherapy on SRS [14]. The findings indicated statistically significant improvements in LUTS, pain, and QoL compared to controls. However, one placebo-controlled trial did not identify statistically significant differences in outcomes with tamsulosin treatment [15]. Similar findings were highlighted with trials on alfuzosin [16-18]. However, one of these trials did not identify differences in QoL with treatment [16]. Monotherapy with terazosin [19] and doxazosin [20] also elicited improvements in urinary and pain symptoms, but not with naftopidil [21]. Dellis et al. [22] compared tamsulosin and alfuzosin against controls in 150 patients, reporting statistically significant differences in the ureteral stent symptom questionnaire (USSQ; P = 0.001) and QoL measures with alpha-blockers versus placebo (P = 0.28); alfuzosin scores were better than those with tamsulosin. Meta-analyses favored alpha-blockers concerning LUTS, pain, and QoL [1,23-25]. However, there is conflicting evidence on their impact on sexual symptoms [24,25]. Liu et al. [26] have elucidated a pathophysiological mechanism for SRS and its treatment in their placebo-controlled trial with alfuzosin in 70 patients, where they also serially measured urinary GAGs over a 3-week treatment period and the 3 weeks after stent removal. There were statistically significant reductions in symptom and biochemical measures at all weekly time points (P < 0.05). Interestingly, urinary GAGs dropped to equivalent levels 3 weeks post-stent removal. Furthermore, GAG levels were strongly positively correlated with urinary symptoms (R2 = 0.65; P < 0.001) and pain scores (R2 = 0.33, P < 0.001). A commonly reported side effect (SE) is postural hypotension and related symptoms (Table 1).
Beta receptors are also important in bladder and urethral relaxation, particularly beta-2 and beta-3 subtypes. Mirabegron is the main beta-3 adrenoceptor agonist that has been trialed, particularly for bladder overactivity and SRS (Table 2). A retrospective case review [27], and two untreated control studies have found benefits with mirabegron [28,29], while only one trial did not identify any therapeutic benefit [28]. A meta-analysis of five studies on mirabegron for SRS concluded that low-quality studies point to symptomatic relief with treatment [30]. A meta-analysis on 546 patients aggregated from five trials evaluating mirabegron for SRS identified that it outperformed controls in eliciting symptom and QoL improvements [31]. Mirabegron was also associated with reduced adjunctive analgesia and hospital readmissions and was well-tolerated with no significant differences in SEs.
Anti-muscarinic drugs used for managing LUTS act by blocking cholinergic signaling at the M2 and M3 receptor subtypes and commonly include oxybutynin, solifenacin, tolterodine, and trospium. These drugs reduced bladder contractility and overactivity, making them viable treatments for SRS (Table 2). A case–control study of solifenacin 10 mg once daily (od) for SRS in 70 patients found significant improvements in all domains of the USSQ (P < 0.05) [32]. One trial compared solifenacin and trospium, with treatment eliciting significant improvements in USSQ scores compared to placebo (P = 0.001); solifenacin was superior to trospium in terms of urinary symptoms, while trospium yielded better results for pain relief [33]. Treatment with tolterodine for 1 month was associated with improvements in urinary symptoms and pain compared to placebo, but not with tamsulosin versus placebo or tolterodine versus tamsulosin in 125 patients [15]. Predictably, anticholinergic SEs were observed but were well tolerated.
PDE5 inhibitors (e.g., sildenafil and tadalafil) are ubiquitously utilized for erectile dysfunction. They increase intracellular cyclic mononucleotides by preventing PDE5-mediated degradation, resulting in urinary tract smooth muscle relaxation, which may help treat SRS (Table 2) [34]. Treatment with sildenafil produced reductions in USSQ domains compared to the untreated controls (P < 0.001) [35]. A meta-analysis of 352 patients from four randomized controlled trial (RCTs) evaluating the effect of PDE5 inhibitors on SRS indicated that sildenafil and tadalafil were associated with improvements in the sexual health domain (P < 0.00001), urinary symptoms (P = 0.03), body pain (P = 0.008), and general health (P < 0.0001) [34]; the PDE5 inhibitor treatment was well-tolerated.
Combination therapies help identify which drugs may be more effective for SRS or specific SRS symptom domains (Table 3). A placebo-controlled trial comparing different treatments evaluated solifenacin, trospium, the antispasmodic hyoscine butyl bromide, and alfuzosin for 2 weeks in 200 patients [36]. There were significant differences in the USSQ urinary symptoms domain between groups, with trospium displaying superiority over other groups (P < 0.01). There was constipation in 46.7% of patients taking solifenacin and in 33.3% of patients on trospium versus other groups (P = 0.048). Dry mouth was a statistically significant SE with anti-muscarinic treatment (P = 0.005). Bhattar et al. [37] carried out a comprehensive placebo-controlled trial in 335 stented patients, investigating silodosin, solifenacin, and tadalafil monotherapies, as well as dual and triple therapies. All treatments were associated with statistically significant reductions in USSQ domains, QoL, and analgesic requirements compared to placebo (all P < 0.001). Silodosin and solifenacin in combination performed well across domains compared to other combinations. Chandna et al. [38] compared mirabegron, solifenacin, and tamsulosin in 150 patients, but no statistically significant differences were observed among groups. A large meta-analysis on alpha-blockers, antimuscarinics, and PDE5 inhibitors for SRS found that all treatments were associated with improvements in symptoms and QoL compared to placebo (Table 4) [39]. Alpha-blockers in combination with antimuscarinics were superior to monotherapy of either drug class. Treatments with PDE5 inhibitors were associated with improvements in sexual health domains, and, importantly, non-inferior in terms of other symptom domains and QoL. However, a controlled study examining the effects of multiple treatments (the non-steroidal anti-inflammatory diclofenac, the anti-spasmodic flavoxate, tolterodine, and doxazosin) in 108 stented patients found no effects [40]. All measures worsened following ureteric stenting, despite treatment.
Three trials compared tamsulosin 0.2 mg od to solifenacin monotherapy and combination therapy with controls and results were conflicting. Treatment was associated with statistically significant improvements in symptoms and QoL compared to controls [41,42]. Furthermore, Lim et al. [41] indicated that combination therapy was associated with a greater magnitude of improvements, followed by solifenacin and tamsulosin monotherapies; whereas Liu et al. [42] concluded its non-inferiority within the treatment groups. However, another trial found no differences in USSQ and QoL scores between treatment and control groups [43]. Trials looking at combination with a higher dose of tamsulosin (0.4 mg) were more positive, with combination therapy being associated with statistically significant improvements in outcome measures versus placebo [44-46]. Only one trial showed tamsulosin-solifenacin combination therapy was superior to monotherapy [44], with the others identifying non-inferiority. Mono- and combination therapy were well tolerated, but one tamsulosin-related trial reported discontinuation [45]. An uncontrolled study observed improvements in urinary symptoms (P < 0.001) and sexual health (P < 0.036) but not in pain scores with tamsulosin and oxybutynin combination therapy compared with monotherapy of either drug [47]. One trial compared tamsulosin monotherapy with tolterodine combination therapy [48]. No statistically significant differences were revealed in outcome measures between the two groups, suggesting no added benefit with combination therapy. A comparison of terazosin 2 mg twice daily (bd) and tolterodine 2 mg od with combination therapy and placebo in 104 patients also identified statistically significant improvements in symptom and QoL measures with treatment, with a greater magnitude observed in the combination group (P = 0.002) [49]. Meta-analyses were equally conflicting with regard to conclusions on whether alpha-blockers are inferior to combination therapies. Several meta-analyses have concluded that alpha-blocker and anti-muscarinic combination therapy was superior to monotherapy in eliciting SRS and QoL benefits [50-53], but other meta-analyses found no difference [54,55]. However, all analyses agreed they are well-tolerated treatments. One meta-analysis of 654 patients found that alpha-blocker and anti-muscarinic monotherapy were non-inferior to each other in efficacy [56].
A head-to-head comparison of tamsulosin and mirabegron with placebo in 161 patients found lower symptom scores with treatment than with placebo, with tamsulosin reportedly superior to mirabegron (P = 0.01). In addition, mirabegron was associated with less adjunctive analgesic use compared to controls (P < 0.001) [57]. A similar study involving 102 patients found no difference in USSQ domains between mirabegron monotherapy and combination therapy with tamsulosin [58]. Comparing tamsulosin and tadalafil treatment revealed favorable outcomes in terms of USSQ scores versus placebo, but tamsulosin was inferior to tadalafil in reducing urinary symptoms, body pain, and sexual health scores [59]. Tadalafil was also associated with reduced analgesic requirement compared to tamsulosin. A comparison of silodosin and diclofenac monotherapy with combination therapy and placebo found that the treatments provided better pain control than placebo [60]. Diclofenac mono- and combination therapy had equivalent benefits, with silodosin inferior to both groups. A placebo-controlled trial observed similar findings when comparing diclofenac and tamsulosin with combination therapy [61].
A randomized single-blinded study comparing mirabegron, solifenacin, and hydration (control group) in 97 patients found that mirabegron and solifenacin were associated with favorable changes in outcome measures with equivalent efficacy [62]. Patients were randomized to oxybutynin and mirabegron to receive treatments for SRS, but no statistically significant differences were found in USSQ scores, which improved over time regardless of treatment [63]. A meta-analysis of 10 trials evaluating solifenacin or combination with tamsulosin reported that solifenacin monotherapy attained improvements in all USSQ domains [64]. Combination with tamsulosin did confer additional benefits but was non-inferior to solifenacin monotherapy. Dry mouth was associated with solifenacin treatment compared to controls (P = 0.02). One trial compared oxybutynin with phenazopyridine, which has a local analgesic effect after being excreted into the urine [65]. No significant differences in outcomes were observed between groups.
A meta-analysis of 280 patients aggregated from three RCTs evaluating PDE5 inhibitors on stent symptoms compared placebo, alpha-blockers, and antimuscarinics and found that they were superior to placebo in improving USSQ scores [66]. They were well tolerated, with tadalafil displaying superiority in sexual health and non-inferiority in other symptom domains.
Pregabalin is derived from the inhibitory neurotransmitter gamma-aminobutyric acid, which acts on certain calcium channels. It has been compared with solifenacin single and combined therapy in two trials [67,68]. Treatment was associated with statistically significant improvements in USSQ scores compared to placebo. Combination therapy was superior to monotherapy. A novel treatment, cannabidiol oil, has been investigated, but no benefits were observed compared to controls [69].
SRSs are associated with significant impairments of QoL. Thus, whilst different variations in stent makeup, including material, have been of clinical utility, as well as intravesical treatments and injections, pharmacotherapy remains the mainstay of SRS treatment (Table 5). The available trials consistently demonstrate the superiority of pharmacotherapy over placebo and controls for SRS. There are clear benefits in terms of urinary symptoms, pain, QoL, and even sexual function. However, the literature is less clear on which drug classes and individual drugs are superior. Mounting individual trials and meta-analyses have been conducted comparing alpha-blockers and anti-muscarinic monotherapy with combination therapy. More studies reported that the effects of combination therapy [39,41,44,50-53] were superior to those of the non-inferiority of monotherapy [46,54,56]. Indeed, some mechanisms have been suggested for the enhanced effects of combination therapy. For instance, PDE5 inhibitor therapy may potentiate the effects of alpha-1 adrenoceptor blockade, further reducing smooth muscle contraction in the bladder and urethra [34]. A graded approach could involve initial monotherapy, with the option for combination therapy if clinical outcomes are suboptimal, guided by patient choice.
Trials comparing different treatments also point to the superiority of certain drugs and their combination use with regard to specific symptom domains. Bhattar et al. [37] compared different treatments and found that silodosin and solifenacin dual therapy controlled urinary symptoms and pain better than monotherapy with either drug, tadalafil monotherapy, triple therapy, and placebo. Two meta-analyses comparing PDE5 inhibitors with alpha-blockers and antimuscarinics demonstrated that sexual health outcomes were better with PDE5 inhibitor treatments and were non-inferior to other drugs used for urinary symptoms and pain [39,66]. This is especially important for sexually active patients, particularly those with longer-staying stents or who require long-term treatments.
Overall, treatments have been well-tolerated. A small number of trials reported statistically significant differences in SEs when treatment was compared to placebo. Constipation was quite common with the antimuscarinics solifenacin (46.7%) and trospium (33.3%, P = 0.048), with dry mouth appearing in 33.3% and 20.0% of patients, respectively (P = 0.005) [36]. Yavuz et al. [57] reported discontinuation in the tamsulosin group due to hypotension (n = 2), with other SEs including ejaculation disorders, as well as in the mirabegron group due to hypertension and flushing (n = 2). Whilst well-tolerated, some of these minor SEs arguably should not occur, especially given that some reports suggested that combination therapy may not provide additional clinical benefits [48,64].
A significant variability in the published trials and meta-analyses that aggregate them was the treatment and follow-up periods, with differences in the order of days to weeks and the lack of evidence from well-designed studies evaluating long-term treatments. This is important because trials with serial outcome measurements throughout the stented period and even after stent removal display differences in the magnitude of clinical effects, indicating greater improvement in the early stented period [41,55]. Thus, clinical effects may be missed with longer follow-up or overstated with early follow-up.
Ureteric stenting is a ubiquitous procedure in urology, but SRS can impact patient QoL and require treatment. There is consistent evidence that adrenergic receptor modulators (alpha-blockers, beta-3 agonists), antimuscarinics, PDE5 inhibitors, and some novel treatments improve SRS and QoL compared to placebo, with more evidence from trials on alpha-blockers and antimuscarinics. Furthermore, increasing evidence supports that combination therapy with these drugs is more beneficial compared to monotherapy, and certain drug classes are more beneficial for different SRS domains. PDE5 inhibitors have positive effects on sexual health without compromising favorable outcomes related to urinary symptoms and pain domains. These treatments are also well tolerated. However, treatment decisions should be shared with the patient, balanced against the severity of symptoms, the duration of stent placement in situ, and potential SEs.