Efficacy and Safety of Muscarinic Antagonists Combined with Adrenergic Alpha-Antagonists in the Medical Expulsion Therapy for Distal Ureteral Stone: A Meta-Analysis

Urinary calculus is one of the most common diseases of the urinary system and is more common in men than in women. It has an estimated total prevalence rate as high as 15% [1, 2] and a recurrence rate of 50% within 5 years after initial onset [3]. The high incidence rate of urinary calculi increases the medical burden annually. In fact, expenditure in the USA is estimated to exceed USD 4 billion by 2030 [4‒6]. Three treatments are commonly used for patients with stones <10 mm: shock wave lithotripsy, medical expulsive therapy (MET), and ureteroscopy. Spontaneous or medicated stone removal is generally recommended for patients without severe clinical symptoms or complete urinary tract obstruction [7]. However, the larger stones make spontaneous passage more difficult and may even cause renal colic. Some studies have suggested that recurrent renal colic may be related to spontaneous stone expulsion [8].

Alpha 1A- and 1D-adrenergic receptors are mainly expressed in the smooth muscle cells of the ureter. Alpha-blockers can reduce urinary tract obstruction by relieving ureteral smooth muscle tension and spasm and are currently one of the standard drugs for the treatment of urinary calculi [9]. The intramural ureter is the narrowest part of the ureter, and the most important obstacle to stone expulsion is at the end of the ureter [10]. Therefore, nearly 70% of urinary tract stones are distal ureteral stones [11]. Due to their proximity to the bladder, lower urinary tract stones often cause bladder irritation and urinary stream interruption. Muscarinic antagonists selectively block M2 and M3 receptors at the level of bladder detrusor muscle cells and reduce bladder afferent nerve activity to reduce involuntary bladder contraction or change contraction threshold, thereby increasing bladder capacity and improving urination urgency [12].

For the treatment of lower ureteral stones, does the combination of alpha-blocker and muscarinic antagonist alleviate lower urinary tract discomfort during stone expulsion? The objectives of this study were to compare the efficacy and safety of a combination of alpha-blocker and muscarinic antagonist with alpha-blocker alone for the removal of lower ureteral calculi and to investigate the capability of this combination in alleviating lower urinary tract symptoms (LUTS) based on existing clinical trials.

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (see online suppl. material for PRISMA Checklist; for all online suppl. material, see https://doi.org/10.1159/000548590) and was registered with PROSPERO (CRD42024598671).

We performed a systematic search of the PubMed, Embase, Cochrane Library, Web of Science, and Chinese databases to identify clinical studies on the use of alpha-blockers combined with muscarinic antagonists for the treatment of patients with lower ureteral stones published from database inception to October 2024. When multiple publications of the same study were found, the latest published data were used. The references included in the studies were manually reviewed. Only randomised controlled trials were included.

We defined study eligibility using the patient population, intervention, comparator, outcome approach, and study design criteria. Studies comparing the efficacy and safety between muscarinic antagonists combined with alpha-blockers and alpha-blockers or muscarinic antagonists alone in medical expulsion therapy for distal ureteral stones were included. The specific inclusion criteria were as follows: (1) studies on humans, (2) original research, (3) enrolled patients with distal ureteric stone measuring ≤10 mm in diameter, and (4) use of alpha-blockers and/or muscarinic antagonists. The exclusion criteria were (1) age <18 years, (2) patients who were pregnant and lactating, (3) urinary tract infection, (4) renal colic more than 24 h, (5) renal insufficiency, (6) single kidney, (7) ureteral stricture, (8) ureteral tumour, (9) history of distal ureter surgery, (10) bilateral ureteral calculi, (11) concomitant upper urinary tract stones, (12) moderate or severe hydronephrosis, and (13) allergic reaction to alpha-blockers and/or muscarinic antagonists.

Data were independently extracted by two authors (C. Chen and Z. Ning). Any disagreement between the two authors was resolved by a third author (H. Ding). The following data were extracted from the included trials: first author, year of publication, intervention group, control group, total number of patients, enrolled patients, treatment duration, and outcome data.

The outcome measures of the included studies were (1) stone excretion rate (SER), which was defined as the percentage of patients with stone excretion at the end of follow-up; (2) stone excretion time (SET), which was defined as the time when the patients self-reported stone expulsion and was accurately confirmed by imaging studies; (3) pain episodes (PEs), which was defined as the frequency of pain attacks during stone removal; (4) Visual Analogue Scale (VAS), which recorded patients’ subjective description of pain [13, 14]; and (5) urine sensation scale (USS), which assessed the urgency of each urination.

Two investigators independently assessed the quality level of the included studies using the Cochrane Collaboration tool [15]. Aspects, such as randomisation, allocation and blinding processes, outcome reporting, and other types of bias were assessed and assigned a grade of low, high or uncertain risk based on quality evaluation. Any disagreement was resolved by discussion with a third reviewer until a consensus was reached. Using the GRADE system, each unique pooled analysis was evaluated and categorised as high, moderate, low, or very low quality of evidence [16].

All statistical analyses were conducted using the Cochrane Collaboration Review Manager software (RevMan 5.3). In the summary analysis, risk ratio (RR) was used to evaluate dichotomous data, such as SER and adverse effects, and weighted mean difference (MD) was used to evaluate continuous data, such as SET, PE, USS, and VAS. We selected two-sided tests, and p < 0.05 was considered to indicate statistical significance. Inconsistency was quantified using the I² statistic. When I² was >50% or p was ≤0.1, which suggested substantial heterogeneity, the random-effects model (DerSimonian-Laird method) [17] was used; otherwise, the fixed-effects model (Mantel-Haenszel method) [18] was applied. Sensitivity analyses were conducted by sequentially excluding each study to validate the reliability of the results and analyse heterogeneity. The presence of possible publication bias was investigated using a funnel plot; if possible, sub-analysis was performed to control this bias.

The database search for Medical Subject Headings and free terms retrieved 42 articles. After removing duplicates, 36 studies were retained; another 12 were removed after reviewing titles and abstracts. Finally, after screening the full text of the remaining 24 articles, 8 clinical trials were included in the systematic review (Fig. 1). Eight trials [13, 14, 19‒24] involving 800 patients compared alpha-blockers in combination with muscarinic antagonists and alpha-blockers or muscarinic antagonists alone. The studies included in our meta-analysis are summarised in Table 1, and their efficacy results are summarised in Table 2.

As shown in Figure 2, the study randomisation method [24] was in order of precedence rather than strict randomisation, and there was a risk of bias in sequence generation. One study [13] described the method for allocation concealment, but other studies did not. Four studies [13, 14, 19, 24] did not clearly explain whether participants were informed, and three studies [14, 19, 24] did not clearly explain whether subjects were informed, so there were unclear performance and detection biases. All studies reported loss to follow-up, withdrawal, and all outcomes, thereby avoiding attrition and reporting biases. All studies were adequately described to exclude other sources of bias. Based on the GRADE system, each unique pooled analysis was categorised as either low or very low-quality evidence (online suppl. Table 1).

Pooled meta-analysis (Fig. 3) showed a significant benefit in SER among patients treated with a combination of muscarinic antagonists and alpha-blockers than among those treated with alpha-blockers alone (RR = 1.13, 95% CI 1.00–1.27; p = 0.04, I² = 51%). Four studies compared SER between combination therapy and muscarinic antagonists. Pooled results showed significantly higher SER with combination therapy than with muscarinic antagonist alone (RR = 1.53, 95% CI 1.26–1.87; p < 0.0001, I² = 0%). Four studies compared SER between alpha-blockers and muscarinic antagonists. Pooled results showed significantly higher SER with alpha-blockers alone than with muscarinic antagonist alone (RR = 1.55, 95% CI 1.27–1.88; p < 0.0001, I² = 0%).

Seven studies reported SET. In Erturhan et al. [19], only the mean value and stone removal time range were given. Using the estimation formula [25], the average ± standard deviation (SD) SETs were 7.5 ± 2.75 and 6.4 ± 2.08 days for the experimental (combination therapy) and control (alpha-blocker monotherapy) groups, respectively. The pooled meta-analysis (Fig. 4) showed no reduction in SET after combination therapy with alpha-blockers and muscarinic antagonists, compared with that after alpha-blocker monotherapy (MD = −1.01, 95% CI −2.62 to 0.59; p = 0.22, I² = 95%).

Among the four studies that reported renal colic occurrence, one study reported on the incidence and significantly reduced pain frequency with alpha-adrenergic antagonist monotherapy than with combination therapy (13.2% vs. 27.9%) [24]; the other three studies reported the average frequency of renal colic [13, 14, 20]. The pooled results (Fig. 5) showed that compared with alpha-blocker monotherapy, combination therapy significantly reduced the number of PEs (MD = −0.75, 95% CI −1.10 to −0.4, p < 0.0001).

In four studies [13, 14, 19, 23], VAS was used to record the pain descriptions of all patients. A score of 0 indicated no pain, and a score of 10 indicated the most severe and unbearable pain. The SD data of the VAS were not reported in Erturhan et al. [19, 23]; therefore, this meta-analysis included only the VAS of the remaining three studies. The pooled results showed that compared with patients treated with alpha-blocker alone, those treated with combination therapy had less pain at 3 days (MD = −3.14, 95% CI −3.44 to −2.84, p < 0.00001); 7 days (MD = −3.77, 95% CI −4.02 to −3.52, p < 0.00001); and 4 weeks (MD = −1.00, 95% CI −1.40 to −0.60, p < 0.00001) (Fig. 6).

Two studies reported the USS [13, 14], which patients used to assess the degree of urination urgency on a five-point scale (1 = no urination, 2 = mild urination, 3 = moderate urination, 4 = severe urination, and 5 = urinary incontinence) [26]. The pooled results showed that the USS score was significantly lower with combination therapy than with alpha-blocker monotherapy at 3 days (MD = −0.93, 95% CI −1.10 to −0.77, p < 0.00001) and 7 days (MD = −0.53, 95% CI −0.68 to −0.38, p < 0.00001). Moreover, the bladder irritation symptoms of patients with urinary urgency significantly improved after the addition of muscarinic antagonists (Fig. 7).

Three studies reported the occurrence of adverse effects, including headache, dizziness, fatigue, orthostatic hypotension, retrograde ejaculation, constipation, dry mouth, and rhinitis. There was no significant heterogeneity (I² = 0%); therefore, a fixed-effects model was used to compare the adverse effects between combination therapy and alpha-blocker alone. The meta-analysis (Fig. 8) showed that combination therapy and alpha-blocker alone had no significant differences in the adverse effects of headache and dizziness (RR = 1.35, 95% CI 0.76–2.42, p = 0.31); fatigue (RR = 1.66, 95% CI 0.56–4.89, p = 0.36); orthostatic hypotension (RR = 0.97, 95% CI 0.14–6.66, p = 0.97); retrograde ejaculation (RR = 0.71, 95% CI 0.23–2.17, p = 0.55); and rhinitis (RR = 0.66, 95% CI 0.09–4.88, p = 0.68) but significantly differed in terms of the adverse effects of constipation and dry mouth (RR = 3.86, 95% CI 1.77–8.44, p = 0.0007).

Among the eight studies included in this meta-analysis, heterogeneity existed among certain outcome indicators. Therefore, a sensitivity analysis was conducted to determine the sources of heterogeneity for each outcome. Sequential exclusion of each study had a significant impact on the SER but not on the SET, indicating instability of results.

The funnel plots showed outliers among the eight studies, indicating potential publication bias for SER or SET (online suppl. Fig. 1, 2).

Currently, the European Association of Urology (EAU)/American Urological Association (AUA) guidelines recommend the use of alpha-blockers for distal ureteral stones [27, 28]. Several systematic reviews and meta-analyses have evaluated the efficacy of alpha-blockers for ureteral stones in the past few years [29‒32]. However, no systematic review or meta-analysis has evaluated the efficacy and safety of muscarinic antagonists combined with alpha-blockers in medical expulsion therapy for distal ureteral stones. This meta-analysis and the pooled results demonstrated significantly higher SER with combination therapy than with alpha-blocker or muscarinic antagonist monotherapy (combination therapy: 79.5% vs. alpha-blocker monotherapy: 68%, p = 0.04; combination therapy: 76.7% vs. muscarinic antagonist monotherapy: 50%, p < 0.00001). Moreover, combination therapy reduced the number of PEs and urinary symptoms. However, there were no significant differences in SET and adverse effects, except for constipation and dry mouth.

Factors affecting ureteral calculi expulsion include stone location, size, number, and structure; ureteral smooth muscle spasm; mucosal oedema or inflammation and ureteral anatomy [33]. The most important obstruction site for passing calculi is the distal end of the ureter, especially the intramural ureter, which is the narrowest part [10]. Considering that the distal ureter is adjacent to the bladder, stones are easily embedded in the stenosed inner wall segment, predisposing patients to renal ureteral colic or accompanying urinary urgency and frequency, similar to overactive bladder (OAB) [33]. Based on these, we investigated whether the combined use of standard drugs for OAB (muscarinic antagonists) and lower ureteral calculi (alpha-blockers) can exert synergistic effects to improve stone removal efficiency, alleviate LUTS caused by lower ureteral calculi, and relieve pain. Alpha-adrenergic antagonists block adrenergic receptors in the bladder to enhance the effects of muscarinic antagonists, which reduce muscarine release from the prostate or urethra and enhance the effects of alpha-blockers [34, 35]. Dual treatment enhances bladder storage and relieves LUTS and pain.

Alpha-blockers are generally used for MET of distal ureteral calculi [36]. In humans, alpha 1A- and 1D-adrenergic receptors are mainly expressed in the smooth muscle cells of the ureter. Alpha-adrenergic blockers act on the distal ureter and relieve lower urinary tract obstruction and irritation by reducing ureteral smooth muscle tension, thereby, causing relaxation and relieving smooth muscle spasm [37]. In addition to accelerating the expulsion of small distal ureteral stones and relaxing spastic smooth muscles, alpha-blockers can provide analgesic effects and reduce LUTS to some extent [38]. Treatment with alpha-adrenergic antagonists is recommended for distal ureteral calculi ≥5 mm, according to the AUA, EAU, and Urological Association of Asia guidelines, and for distal ureteral calculi <10 mm, according to the Canadian Urological Association and the National Institute for Health and Care Excellence [39, 40]. In this meta-analysis, the mean stone size of all patients was 7.1 mm, which is consistent with the recommended guidelines on the use of alpha-adrenergic antagonists for stone expulsion. However, in a study by Hermans et al.[41], the average number of analgesics taken before distal ureteral stone passage was three in the group treated with tamsulosin (n = 50) and seven in the placebo group (n = 50), underscoring the fact that although tamsulosin can alleviate pain to a certain extent, the demand for analgesics remained high. According to the EAU guidelines, the standard treatment for relieving renal and ureteral colic is intake of nonsteroidal anti-inflammatory drugs, such as diclofenac sodium [42]. Maldonado found that although nonsteroidal anti-inflammatory drugs, such as diclofenac and indomethacin suppositories, can alleviate acute pain from distal ureteral stones, the effect was slow in many patients, the root cause of pain was not resolved and gastrointestinal adverse effects were common [43].

Muscarinic antagonists selectively block M2 and M3 receptors on the detrusor muscle cells of the bladder, reduce involuntary bladder contractions or alter contraction thresholds, decrease afferent bladder nerve activity, and increase bladder volume. To reduce urinary urgency and frequency, address urinary incontinence, and improve the health-related quality of life [12, 44, 45], muscarinic antagonists are commonly used to treat patients with OAB [46]. Renal ureteral colic, urinary urgency and frequency and pain on the glans penis associated with the distal ureter may be controlled by muscarinic antagonists [25, 47]. Kaplan found that compared with placebo, the combination of tolterodine and tamsulosin significantly improved urge incontinence (−0.88 vs. −0.31, p = 0.005); episodes of urinary urgency without urinary incontinence (−3.33 vs. −2.54, p = 0.03) and urinary frequency for 24 h (−2.54 vs.−1.41, p < 0.001) and per night (−0.59 vs.−0.39, p = 0.02) in men with moderate to severe LUTS [48]. Meanwhile, inhibition of glandular secretion is the main adverse effect of muscarinic antagonists. The feeling of dry mouth prompts patients to drink a lot of water, which increases urine volume and flow and may be beneficial to stone excretion.

Three systematic reviews have evaluated the effectiveness of mirabegron for treating ureteral stones [49‒51], and the pooled results demonstrated that mirabegron significantly increased SER in patients with distal ureteral stones. This meta-analysis showed that constipation and dry mouth were the main adverse effects of combination therapy, compared with alpha-blocker alone. Dry mouth and constipation are common antimuscarinic drug-related adverse events. In the future, reducing these toxic adverse effects will enable patients to have better tolerance of combination therapy. Existing evidence suggests that β3-adrenergic receptor agonists, such as mirabegron and vibegron, have a lower incidence of dry mouth than antimuscarinics, such as tolterodine) [52, 53]. Based on these reasons, the combination of new β3-adrenergic receptor agonists and alpha-blockers is a promising treatment option for distal ureteral stones.

Combination therapy with alpha-blocker and muscarinic antagonist not only improved bladder irritation but also significantly alleviated renal and ureteral colic caused by stones. Among the clinical trials on tamsulosin alone to assist in the expulsion of 5–10-mm distal ureteral calculi, the reported frequencies of renal ureteral colic were 1.60 ± 1.0 [54], 1.70 ± 1.2 [47], 1.60 ± 1.0 [54], and 2.90 ± 0.90 [55] times. In the articles included in this meta-analysis [13, 14, 20], the PEs among patients treated with tamsulosin alone and combination therapy were 3.2 ± 2.1 and 2.8 ± 1.8 times, 2.27 ± 0.91 and 1.39 ± 1.34 times, and 2.25 ± 0.90 and 1.38 ± 1.37 times, respectively. These data indicated that pain was less with combination therapy than with tamsulosin alone. The VAS was significantly lower in the combination therapy group than in the alpha-blocker monotherapy group. Moreover, the lower mean number of PEs and VAS with combination therapy than with monotherapy make it reasonable to speculate that the combination of alpha-blockers and muscarinic antagonists can relieve the onset pain from renal ureteral colic. In Erturhan et al. [19], although the SD data on PE and VAS were missing, the data showed a trend of less degree of colic with combination therapy than with alpha-blocker alone (VAS: 4.1 vs. 4.7). Chu et al. [24] only recorded the number of patients requiring meperidine (Demerol) analgesia for severe renal colic in the combination therapy and alpha-adrenergic antagonist alone (0 vs. 5), respectively. Based on these available data from the two articles, pain control and alleviation of patient discomfort were more effective with combination therapy than with alpha-blocker alone.

This meta-analysis had some inevitable limitations. First, due to the small number of included studies and large heterogeneity of the partial results, the I² statistic was not effective enough. Second, majority of the randomised studies in this systematic review were small single-centre studies that reported insufficient raw data, which precluded subgroup analyses by stone size and drug type and limited the strength of our conclusions. Therefore, multicentre, randomised, placebo-controlled trials are needed for further validation. Third, like any systematic review, our analysis was limited by the data included in the studies, and we had to rely as much as possible on imperfect datasets. Nevertheless, to the best of our knowledge, these were the best available data that showed the effectiveness of combining alpha-blockers and muscarinic antagonists to improve the symptoms of patients with lower ureteral stones. To support our findings, future clinical trials may further investigate the use of serum biomarkers, such as C-reactive protein, which was reported to be associated with MET failure at relatively high levels [56].

For patients with solitary lower ureteral stones measuring less than 10 mm, the combination of adrenergic alpha-blockers and muscarinic antagonists appears to be more effective than alpha-blocker monotherapy in enhancing stone expulsion, mitigating renal colic, and alleviating LUTS. Although stone expulsion time is not significantly impacted, the increased risk of dry mouth and constipation must be weighed against the potential clinical benefits. Future high-quality, multicentre trials are warranted to confirm these findings and to explore better tolerated combinations, such as beta-3 agonists paired with alpha-blockers.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This study was supported by the Science and Technology Project of Gansu Province (21JR1RA119), the Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital (CY2021-MS-B03), and Gansu Province Healthcare Industry Research Project (No. GSWSQN2024-11). The funder had no role in the design, data collection, data analysis, and reporting of this study.

H.D. contributed to the study conception and design. Material preparation was performed by C.C., C.M., S.Z., and N.F. Data collection and analysis were performed by Z.N., Z.H., C.C., S.Z., C.M., and N.F. The first draft of the manuscript was written by N.F., C.C., S.Z., C.M., and H.D. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Chuanjian Chen and Chunhao Mo contributed equally to this work.

All data that support the findings of this study are included in this article and its online supplementary material. Further enquiries can be directed to the corresponding author, Hui Ding ([email protected]).