Neurogenic lower urinary tract dysfunction (NLUTD) is a major concern for patients with spinal cord injury (SCI). It can cause renal function deterioration and renal failure, urinary tract infection, and vesicoureteral reflux [1]. Therefore, the goals of care in this population are the protection of the upper urinary tract and prevention of renal damage by increasing detrusor capacity and lowering detrusor pressure [2].

Successful pharmacological management of NLUTD leads to an improvement in the activities of daily living, psychosocial well-being, and long-term persistence, along with the adverse effects of drugs [3]. In current clinical guidelines, antimuscarinic agents such as propiverine, tolterodine, oxybutynin, fesoterodine, and solifenacin are often initially prescribed. Antimuscarinics have been proven to increase bladder capacity and detrusor compliance and to lower the risk of upper urinary tract damage, thus improving patients’ quality of life [4]. However, people with SCI require an increased dosage of antimuscarinic agents to obtain sufficient therapeutic effect, which, in turn, may exacerbate the adverse events (i.e., dry mouth, constipation, blurred vision, and cognitive impairment). Due to lack of efficacy and the side effects of the drugs, the administration of antimuscarinics for the treatment of NLUTD in patients with SCI often leads to poor treatment compliance, resulting in the termination of therapy [5].

Mirabegron, a β3-adrenoceptor selective agonist, has been proven to have a similar efficacy as antimuscarinics. Because of its different mode of action from that of antimuscarinics, this agent does not lead to antimuscarinicrelated adverse events [6]. Owing to these advantages, the frequency of mirabegron administration for SCI patients with NLUTD has increased over the years. A study showed improvements in urodynamic and clinical parameters when switching from conventional antimuscarinic treatment to mirabegron monotherapy for a short period of time [7]. However, objective evidence to prove the effectiveness of drug when prescribed for long-term use in people with SCI is currently unavailable. In this study, we tested the hypothesis that adding mirabegron to conventional antimuscarinic therapy in SCI patients with NLUTD would be effective in the long term.

NLUTD is a common sequela of neurological disorders including SCI. It has been reported that over 80% of individuals with SCI experience impaired bladder function, including detrusor overactivity and detrusor sphincter dyssynergia, within 1 year after injury [16]. The high prevalence and severity of NLUTD negatively affect all aspects of the patient’s life and the importance of the proper management of NLUTD in the long-term is now being recognized in neurological practice [17]. The goals of management are to prevent urinary tract infection and autonomic dysreflexia, maintain dryness to improve quality of life, and preserve the upper urinary tract by increasing detrusor capacity and lowering intravesical pressure [18].

The current mainstay of pharmacotherapy for NLUTD has focused on antimuscarinic agents for several decades [19]. The primary action of antimuscarinics is to inhibit the effects of acetylcholine at the postganglionic autonomic receptors on detrusor muscle cells, which results in detrusor relaxation, lower intravesical pressure, and storage symptoms [4]. These therapies have been proven to ameliorate bladder storage function and improve urodynamic variables in individuals with NLUTD [20]. However, despite their well-established effect, the rate of discontinuation of these drugs is high for several reasons. First, they affect organs outside the lower urinary system, including the gastrointestinal system, eyes, and central nervous system, resulting in adverse events such as dry mouth, constipation, blurred vision, and deterioration of cognition in the elderly [21,22]. Second, antimuscarinics are often administered at higher doses to patients with SCI than to the individuals with overactive bladder (OAB), resulting in more severe side effects and termination of therapy [23].

Mirabegron, a β3-adrenoceptor selective agonist, was recently licensed for the treatment of OAB and is a recognized novel pharmacological compound with a better efficacy/side-effect profile to overcome the limitations of antimuscarinics [24]. Among the three subtypes of β adrenoceptors (β1, β2, and β3) in human detrusor muscle, β3 adrenoceptors account for 97% of total β adrenoceptor mRNA [25], and activation of β3 adrenoceptors elicits detrusor relaxation [24]. Therefore, it is hypothesized that mirabegron could increase bladder capacity without causing antimuscarinic side effects and is expected to play a vital role in the management of NLUTD in patients with SCI. Maman et al. [6] reported that mirabegron at a dose of 50 mg had a similar efficacy to that of antimuscarinics, with a lower incidence of dry mouth and constipation in individuals with OAB.

The urodynamic effects of antimuscarinic agents in OAB and NLUTD have been well documented in previous studies [26], but the clinical experience and evidence of mirabegron efficacy as demonstrated by UDS are still inadequate. Matsukawa et al. [27] and Vecchioli Scaldazza and Morosetti [28] reported a significant increase in cystometric capacity by an average of 37 mL and 41 mL, respectively, in women with OAB who received mirabegron 50 mg once a day for 12 weeks. In a study involving men with OAB, mirabegron add-on therapy with tamsulosin significantly increased cystometric capacity (by 24%, from 170 to 212 mL) [29]. Wollner et al. [7] conducted a retrospective study by including 12 people with SCI who took mirabegron for at least 6 weeks and observed improvements in urodynamic variables: cystometric capacity (+54 mL), bladder compliance (+17 mL/cmH₂O), and maximal detrusor pressure (−16 cmH₂O). Krhut et al. [30] examined 66 people with SCI or multiple sclerosis who were randomized to mirabegron 50 mg once a day group and placebo. After 4 weeks, the change from baseline in cystometric capacity and compliance was +55 mL and +24 mL/cmH₂O, respectively.

Theoretically, mirabegron add-on therapy to conventional antimuscarinic therapy may increase efficacy compared to the sole increase in the dosage of antimuscarinics and possibly reduce antimuscarinic burden because they block completely different bladder receptors, and mirabegron does not affect muscarinic receptors outside the lower urinary system. In our treatment concept, we added mirabegron to pre-existing anticholinergics for patients who had been refractory to maximally tolerated anticholinergic therapy and considered lowering the number or dose of pre-existing anticholinergics, especially for patients who experienced antimuscarinic side effects through outpatient clinic visit. As a result, the subjects showed a significant increase in cystometric capacity, reflex volume, and bladder compliance. The presence of leakage during filling cystometry was significantly reduced. Although maximal detrusor pressure also decreased after adding mirabegron, the difference was not significant. In addition, the number of antimuscarinics prescribed showed a decreased tendency (Table 2). The recorded antimuscarinic side effects were dry mouth (n=5, 16%) and constipation (n=2, 6%). The lessening of antimuscarinic burden was noted in these patients and no antimuscarinic adverse effects were observed after adding mirabegron.

The present study has several limitations. Because of the retrospective design of the study, data regarding adverse events or adherence/persistence were unavailable. For the further clinical application of long-term mirabegron add-on therapy, studies on side-effect profiles and adherence to multidrug therapy are required. The heterogeneity of composition of antimuscarinics also pertains to the limitations of the present study. However, it was inevitable in the long-term clinical situation to further increase efficacy, while keeping the side effects profile low. Furthermore, this study is limited by the relatively small sample size. Although mirabegron has emerged as an alternative to overcome the limitations of antimuscarinic agents, the most widely prescribed medications as first-line therapy are antimuscarinics according to international guidelines, and many people still benefit from them. The relatively high cost and concerns about cardiac side effects may also restrict the use of mirabegron. Our results suggest that mirabegron should be considered as a complement and not as a substitute for conventional therapy. Further factors which may contribute, in part, to the treatment effect such as muscle relaxants, concomitant medication, smoking, and alcohol use should be considered in future studies.

In conclusion, in patients with SCI and NLUTD, who had previously been exposed to antimuscarinic therapy, adding a long-term β3 adrenoceptor selective agonist provided urodynamic improvements in efficacy compared with previous therapies. Compared to previous studies, our study demonstrated the persistence of mirabegron efficacy for more than 6 months and the superiority of add-on therapy with mirabegron over conventional antimuscarinic therapy in patients with chronic SCI, based on UDS. We anticipate that the results of this study would provide the basis for further well-designed prospective trials with mirabegron and may help patients with NLUTD.