Spontaneous stone expulsion occurs in about 50% of patients, but problems like ureteral colic, UTIs, and hydronephrosis might occur. The use of adjuvant drugs in MET for distal ureteral stones has shown increased stone clearance rates and decreased pain and complications [8].

Highly selective alpha-1A-adrenoceptor blockers, such as silodosin, have emerged as a way to reduce cardiovascular side effects while maintaining effectiveness in the urinary tract. However, these drugs can still cause unwanted effects such as postural hypotension, anejaculation, and dizziness [9].

To address the need for therapeutic agents with different mechanisms of action and fewer side effects, the study explores the use of beta-3 adrenoceptor agonists for ureteral dilation [10].

Real-time quantitative PCR studies have shown that the dilated distal ureter has fewer beta-3 adrenoceptors compared to a healthy part, suggesting the importance of these receptors in ureteral dilation. [11] Based on this data, the study was designed as a prospective, randomized trial to evaluate the efficacy and safety of tamsulosin, mirabegron, or both as MET for distal ureteral stones.

In this study, we show stone expulsion rates in different treatment groups. In the silodosin group (Group A), stone expulsion was reported in 20 out of 35 patients (57.1%), while in Group B, which received mirabegron, it was observed in 18 out of 35 patients (51.4%). In Group C, which received a combination of both medications, stone expulsion was reported in 33 out of 35 patients (94.3%). The stone expulsion rate was significantly higher in Group C compared to Groups A and B, with P-values of 0.04 and 0.004, respectively. However, there was no statistically significant difference in stone expulsion rates between Group A and Group B, with a P-value of 0.745.

Previous studies have reported stone expulsion rates for silodosin ranging from 66 to 84% for stone sizes less than 10 mm, which is higher than the rates observed with placebo, naftopidil, or tamsulosin [12, 13]. Our finding of a 57.1% stone expulsion rate in the silodosin group for patients with stone sizes between 6 and 9 mm is consistent with the results reported by Itoh et al. [14].

Solakhan et al. conducted a study on patients with distal intramural ureter stones and found that mirabegron resulted in a stone expulsion rate of 73.5%. They observed a significant difference in stone sizes less than 10 mm between the mirabegron group and the control group. However, contrary to our findings, Tang et al. and Solakhan et al. [15, 16] did not find significant effects when combining mirabegron with tamsulosin or diclofenac for stones larger than 5 mm. This divergence in results might be attributed to the use of different drug combinations involving mirabegron in those studies.

Bayar et al. conducted a randomized multicenter research study to evaluate the effectiveness of mirabegron and silodosin in patients with stones ranging from 4 to 10 mm. They reported similar rates of stone expulsion across all groups since they established a control group instead of a combination group, which contrasts with our study [17].

In our current study, Group C, which received combination therapy, exhibited a significantly higher stone expulsion rate of 94.3%. This outcome can be attributed to the administration of two drugs with distinct mechanisms of action.

The average expulsion time (standard deviation) for Groups A, B, and C was 14 ± 2.3 days, 11 ± 3.1 days, and 7 ± 2.2 days, respectively. The combination group (C) had a significantly shorter stone expulsion time compared to the silodosin group (A) and mirabegron group (B) (p = 0.001 and p = 0.04, respectively). Solakhan et al. reported mean stone expulsion times of 7.64 days and 9.2 days for the mirabegron group in distal ureteric stone in different studies. Consistent with our findings, some trials reported stone expulsion times ranging from 10.27 to 14.8 days in the silodosin group for distal ureteric stones [13, 14, 18]. However, other studies reported shorter expulsion times, ranging from 8.09 to 9.4 days [19, 20].

The numbers of renal colic episodes and the need for analgesics.

Ureteric colic occurs when there is increased pressure within the ureter proximal to the site of obstruction. Alpha-adrenergic receptor (AR) antagonists block the C fibers responsible for mediating ureteric colic [21].

Several in vivo studies in animals have demonstrated the relaxant effect of beta-3 agonists on the ureter, leading to a significant decrease in intraluminal pressure. Mirabegron, a beta-3 agonist, relaxes ureteric musculature and dilates the ureteral lumen by stimulating beta-3 adrenoreceptors. This mechanism of action makes mirabegron a potentially effective and safe alternative for medical expulsive therapy (MET), which operates through different pathways [22].

The mirabegron group (B) had a lower frequency of renal colic episodes in comparison to the silodosin group (A) (0.8 ± 0.06 vs. 1.6 ± 1.1, p = 0.001). The combination group (C) had an even lower frequency (0.6 ± 0.2), and fewer analgesics were required (P = 0.001) Recent clinical trials have identified a notable distinction between the mirabegron group and control groups regarding the occurrence of renal colic episodes and the requirement for analgesics in patients with distal ureter stones [15, 17]. Kumar et al. documented an average of 0.8 pain episodes in the silodosin group [18].Substantial evidence suggests that the administration of mirabegron, in combination with other alpha-adrenoreceptor antagonists, for the treatment of distally located ureteral stones is associated with improved stone-free rates (SFR), reduced stone expulsion intervals, and fewer colic attacks [23,24,25,26].

In our study, no serious adverse effects were observed because both drugs are safe and well tolerated. Anejaculation occurred in 17 out of 23 patients (73.9%) in group A and 21 out of 25 patients (84%) in group C, but no patient discontinued the treatment. The condition was reversible and resolved quickly after stopping the treatment.

Blood pressure and pulse rate did not significantly alter in our study patients. Our findings are supported by a review of the literature, which reveals that a 50 mg dose of mirabegron is not connected to changes in blood pressure or heart rate [27].

Silodosin, which is a highly selective α1A-AR blocker, demonstrates a better stone expulsion rate (57.1%) compared to mirabegron (51.4%). However, mirabegron has the advantage of reducing the stone expulsion time (11 ± 3 vs. 14 ± 2.3 days), numbers of renal colic, and the analgesia requirements. It also has a favorable safety profile with low complications. Therefore, mirabegron shows promise as a medical expulsive therapy (MET) agent for patients with distal ureteric stones.

When silodosin and mirabegron are combined, there is an even higher stone-free rate (94.3%), shorter expulsion times (7 ± 2.2 days), and a reduction in episodes of renal colic (0.6 ± 0.2). This combination therapy offers the advantage of fewer colicky episodes as well. Therefore, for distal ureteric stones with a diameter of ≤ 10 mm, it is recommended to consider the addition of silodosin as a therapy, and mirabegron can be administered to help reduce numbers of renal colic and the analgesia requirements.

The limitations of our study are that non-contrast CT was not done in the follow-up period to assess the stone-free rate due to financial necessity. Silodosin is a labeled medication for lower ureteric stone, but mirabegron is not yet labeled for the treatment of lower ureteric stone. Increases the cost of treatment due to the combination of drugs. Additionally, the small sample size and single-center work suggest the need for larger studies to be conducted.