The efficacy and safety of adrenergic alpha-antagonists combined with PDE5 inhibitors in the medical expulsive therapy for unilateral distal ureteral stones: a systematic review and meta-analysis

Abstract

Background

Distal ureteral stones are a common urological condition, causing significant morbidity. While medical expulsive therapy (MET) using α-adrenergic receptor antagonists (α-ARAs) or phosphodiesterase-5 (PDE5) inhibitors has been widely studied, the efficacy and safety of their combination remain debated. This study aimed to evaluate the efficacy and safety of this combination therapy compared with α-ARAs alone.

Methods

A systematic search was conducted on PubMed, Embase, the Cochrane Library, Web of Science, and Chinese databases to identify clinical studies published up to November 02, 2025, involving patients with distal ureteral stones treated with PDE5 inhibitors in combination with α-ARAs.All analyses were performed using the Cochrane Collaboration Review Manager software (RevMan 5.4).

Results

A total of eight randomized controlled trials (RCTs) involving 1,202 patients were included, with 1,029 patients ultimately enrolled in the meta-analysis. For distal ureteral stones, the stone expulsion rate (SER) was significantly higher in the combination therapy group than in the α-ARA monotherapy group [risk ratio (RR) =1.25, P<0.001]. The mean stone expulsion time was also significantly shorter in the combination group [standardized mean difference (SMD) =−0.73, P<0.001]. In terms of pain episodes, combination therapy showed a trend toward reducing the number of pain attacks and the need for analgesics. However, the pooled analysis for pain episodes was limited by substantial heterogeneity. Additionally, there were no significant differences between the two groups in terms of adverse events such as headache, dizziness, or hypotension. However, an association with a higher trend of back pain was observed [odds ratio (OR) =1.64, P=0.02], which lost statistical significance in the sensitivity analysis (P=0.06).

Conclusions

This meta-analysis indicates that compared with α-ARAs monotherapy, combination therapy significantly improves the SER, shortens stone expulsion time, and reduces the need for analgesics. The pooled analysis for pain episodes was limited by substantial heterogeneity and must be interpreted with caution. Regarding safety, there were no significant differences between the two groups for most adverse events; however, an association with a higher risk of back pain was observed, a finding that must be interpreted with caution.

Highlight box.

Key findings

• For unilateral distal ureteral stones <10 mm, combining α-adrenergic receptor antagonists (α-ARAs) and phosphodiesterase-5 (PDE5) inhibitors improves the stone expulsion rate, shortens expulsion time, and reduces analgesic use compared to α-ARAs monotherapy. Narrative synthesis suggests fewer pain episodes, despite high heterogeneity. A potentially higher back pain risk was noted, requiring cautious interpretation.

What is known and what is new?

• α-ARAs are the standard first-line medical expulsive therapy (MET). While PDE5 inhibitors independently aid expulsion, their combined clinical efficacy remained uncertain.

• This meta-analysis demonstrates that dual therapy synergistically enhances expulsion efficiency, offering superior clearance rates and faster passage than standard monotherapy.

What is the implication, and what should change now?

• Combination therapy is an optimized, highly effective MET strategy for patients seeking to avoid surgery. Clinicians should consider this dual-drug regimen to maximize expulsion success, provided they weigh individual risks and counsel patients on mild adverse events like back pain.

Introduction

Urinary stones are a global health problem, and the incidence of urinary stones has been increasing in recent decades (1). Men are more likely to develop urinary stones than women (2). As the size of the stone and its distance from the distal ureteral orifice increase, the possibility of spontaneous stone expulsion decreases (3). It has been reported that the natural expulsion rate of distal ureteral stones <5 mm is approximately 68%, while that of stones 5–10 mm is approximately 47% (4). Currently, ureteral stones can be treated with medication, surgery, or extracorporeal shock wave lithotripsy. Compared with medical treatment, surgical treatment and extracorporeal shock wave treatment are not only costly but also cause damage to the ureter (5-7). For stones <10 mm, medical treatment is recommended for pain relief and stone expulsion to increase the probability of natural stone expulsion and avoid surgical treatment (8). Recently, a systematic review and meta-analysis by Belkovsky et al. evaluated the comparative efficacy of tadalafil monotherapy versus tamsulosin monotherapy, reporting similar stone expulsion rates (SERs) for both single agents (9). However, whether combining these two classes of drugs offers superior efficacy compared to monotherapy alone remains a distinct clinical question. Specifically, for the treatment of distal ureteral stones, can the combination of α-adrenergic receptor antagonists (α-ARAs) and phosphodiesterase-5 (PDE5) inhibitors enhance the efficiency of stone expulsion without causing additional adverse reactions? This study aims to compare the efficacy of α-ARAs combined with PDE5 inhibitors and the use of α-ARAs alone in the expulsion of distal ureteral stones based on existing clinical trials. We present this article in accordance with the PRISMA reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-1-982/rc) (10).

Methods

This study was registered in PROSPERO (CRD420251006756).

Search strategy and selection criteria

We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, and Chinese databases from the establishment of the databases to November 02, 2025, for clinical studies on patients with distal ureteral stones usingα-ARAs and PDE5 inhibitors. When multiple publications of the same study were found, the latest data were used. The reference lists of relevant journals, books, and additional studies were manually screened. Only randomized controlled trials (RCTs) were included. For the specific search strategy, please refer to the Appendix 1.

The inclusion criteria were as follows: (I) human studies; (II) reporting of original research; (III) inclusion of patients with distal ureteral stones ≤10 mm in diameter; (IV) use of α-ARAs and/or PDE5 inhibitors.

The exclusion criteria were as follows: (I) age <18 years; (II) pregnant and lactating patients; (III) urinary tract infection; (IV) severe or intractable pain requiring immediate surgical intervention; (V) renal insufficiency; (VI) single kidney; (VII) ureteral stricture; (VIII) ureteral tumor; (IX) history of distal ureteral surgery; (X) bilateral ureteral stones; (XI) associated upper urinary tract stones; (XII) moderate or severe hydronephrosis; (XIII) allergy to α-ARAs and/or PDE5 inhibitors.

Data extraction

Three independent reviewers (C.C., C.M., and N.F.) screened the studies, abstracts, and full texts. In case of disagreement, consensus was reached through discussion. Two investigators (C.M. and Z.N.) independently extracted the trial data. In case of disagreement, a third reviewer (H.D.) helped to resolve it.

A comprehensive data audit was performed by the authors. This audit involved a full re-verification of all extracted data points from every included study to ensure accuracy and methodological rigor. All meta-analyses presented in this manuscript were subsequently re-run based on this finalized and verified dataset.

Outcomes

The following information was extracted from the included trials: first author, year of publication, intervention group, control group, total number of patients, number of enrolled patients, duration of treatment, and outcome data. The following outcome indicators were defined: (I) SER: the proportion of patients with stone expulsion at the end of follow-up; (II) stone expulsion time: the time reported by patients for stone expulsion (more accurately confirmed by imaging); (III) number of pain episodes: the number of pain episodes during stone expulsion; (IV) dosage of analgesics: the dosage of analgesics used for each pain episode; (V) adverse reactions: Adverse reactions that occurred in patients during the treatment process were recorded.

Quality assessment of evidence

Two investigators independently assessed the quality level of the included studies using both the Cochrane Collaboration’s tool (11) and the modified Jadad scale. Regarding the Cochrane tool, the aspects of assessment included randomization, allocation, blinding process, outcome reporting, and other types of bias. Each aspect was assigned a low, high, or uncertain risk based on the quality assessment results. Additionally, the methodological quality was quantitatively evaluated using the modified Jadad scale, which assesses randomization, allocation concealment, blinding, and withdrawals/dropouts. The scale ranges from 0 to 7 points, with a score of ≥4 indicating high quality. The detailed quality assessment results are summarized in Figure 1 and Table 1. In case of disagreement, consensus was reached through discussion. Furthermore, the certainty of evidence for the main outcomes was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The evidence was graded as high, moderate, low, or very low based on risk of bias, inconsistency, indirectness, imprecision, and other considerations.

Figure 1.

Quality assessment by the ROB tool. ROB, risk of bias.

Table 1. The quality assessment outcome of each RCT using the modified Jadad scale.

Study	Randomization (0–2)	Allocation concealment (0–2)	Blinding (0–2)	Withdrawals (0–1)	Total score
Diab 2025 (12)	2	2	2	1	7
Dogha 2025 (13)	2	2	0	1	5
Samir 2020 (14)	2	2	2	1	7
Jayant 2014 (15)	2	2	2	1	7
Rahman 2018 (16)	2	2	0	1	5
Kumar 2014 (17)	2	2	0	1	5
Gnyawali 2020 (18)	2	0	0	1	3
Tayab 2022 (19)	2	0	0	0	2

RCT, randomized controlled trial.

Statistical analysis

All analyses were performed using the Cochrane Collaboration’s Review Manager software (RevMan 5.4) (20). In the pooled analysis, the risk ratio (RR) with its 95% confidence interval (CI) was used to evaluate the primary outcome of SER, while the odds ratio (OR) was used for other binary data (such as adverse events). The mean difference (MD) was used to evaluate continuous data, and the standardized mean difference (SMD) was used for indicators with non-uniform units. All tests were two-sided. If the heterogeneity test (I²>50% or P≤0.1), a random effects model (DerSimonian-Laird method) was applied; otherwise, a fixed effects model (Mantel-Haenszel method) was applied. Sensitivity analysis was performed to verify the reliability of the results and to analyze heterogeneity. For outcomes demonstrating extreme and unexplained heterogeneity (I²>75%) that could not be resolved by subgroup analysis, we refrained from calculating a pooled effect estimate and instead conducted a narrative synthesis to describe the findings qualitatively. For multi-arm studies that provided more than one relevant comparison, we treated each comparison as an independent study. Specifically, the trial by Dogha 2025 (13), which included four arms (A: silodosin; B: tamsulosin; C: silodosin + tadalafil; D: tamsulosin + tadalafil), was split into two independent comparisons: Dogha 2025A (Group C vs. Group A) and Dogha 2025B (Group D vs. Group B). Regarding missing outcome data, a complete case analysis approach was utilized. Only patients with documented outcomes were included in the pooled analysis, and no data imputation techniques were applied.

Results

Study selection and characteristics

A total of 207 records were initially identified (204 from databases, and 3 via citation searching). Before screening, 90 duplicate records and 84 records for other reasons were removed. Subsequently, 33 unique records were screened. After excluding 11 non-original studies during initial screening, 22 full-text articles were assessed for eligibility. Of these, 14 were excluded due to ineligible interventions (n=9), populations (n=4), or study design (n=1). Ultimately, 8 studies were included in the meta-analysis (Figure 2). The baseline characteristics of the included trials are summarized in Table 2. Excluded studies and reasons are detailed in Table S1. Notably, the multi-arm trial by Dogha 2025 (13) provided two independent, relevant comparisons. Therefore, our primary analysis included 9 comparisons from these 8 trials. These 8 trials (12-19) involved 1,202 patients, with 1,029 patients actually included, comparing the efficacy of α-ARAs combined with PDE5 inhibitors and the use of α-ARAs alone. The experimental group received combination therapy, and the control group received α-ARAs alone. The detailed clinical outcomes and reported adverse events extracted from each included study are summarized in Table 3.

Figure 2.

Flow diagram of the literature search process based on PRISMA guidelines. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 2. Baseline characteristics and intervention protocols of the included studies.

Study	Year of publication	Country	Study design	Sample size	Patient population	Interventions	Treatment duration (Max follow-up)	Stone size
Muhammad Tayab (19)	2022	Pakistan	RCT	158	Sex: not reported. Mean age (± SD) (years): Group A: 32.75±9.01; Group B: 32.84±10.00	Group A: tamsulosin 0.3 mg + tadalafil 8 mg. Group B: tamsulosin 0.3 mg. (Corticosteroid: no)	Max 3 weeks	Mean stone size (mm) (mean ± SD): diagnosis: CT/USG; follow-up: not specified (CT for doubts); Group A (tamsulosin + tadalafil): 7.42±1.22; Group B (tamsulosin): 7.33±1.12
Mohamed Mahmoud Dogha (13)	2025	Egypt	RCT	180	Sex (total): 124 M/56 F. Mean age (± SD) (years): Group A: 36.7±9.83; Group B: 36.6±11.32; Group C: 37.5±10.34; Group D: 37.2±9.98	Group A: silodosin 8 mg. Group B: tamsulosin 0.4 mg. Group C: silodosin 8 mg + tadalafil 5 mg. Group D: tamsulosin 0.4 mg + tadalafil 5 mg. (Corticosteroid: no)	Max 4 weeks	Stone size (mm) (mean ± SD): diagnosis: CT; follow-up: KUB (CT for radiolucent); Group A (silodosin): 6.80±1.76; Group B (tamsulosin): 6.50±1.77; Group C (silodosin + tadalafil): 6.70±1.82; Group D (tamsulosin + tadalafil): 6.60±1.51
Tamer Diab (12)	2025	Egypt	Double-blind RCT	128	Sex (total): 83 M/45 F. Mean age (± SD) (years): Group I: 37.5±7.7; Group II: 35.7±6.8; Group III: 39.2±7.9	Group I: silodosin 8 mg. Group II: tadalafil 5 mg. Group III: silodosin 8 mg + tadalafil 5 mg. (Corticosteroid: no)	Max 4 weeks	Stone size (mm), median (range): diagnosis: CT; follow-up: CT; Group I (silodosin): 6.5 (5.2–9); Group II (tadalafil): 6.5 (5.2–9); Group III (combined therapy): 6.5 (5.2–9)
Kumar Jayant (15)	2014	India	Double-blind RCT	244	Sex (total): 132 M/112 F. Mean age (± SD) (years): Group A: 36.45±10.36; Group B: 37.23±12.54	Group A: tamsulosin 0.4 mg. Group B: tamsulosin 0.4 mg + tadalafil 10 mg. (Corticosteroid: no)	Max 4 weeks	Mean stone size (mm) (mean ± SD): diagnosis: NCCT; follow-up: NCCT; Group A (tamsulosin): 6.72±1.44; Group B (tamsulosin + tadalafil): 7.05±1.62
Mohamed Samir (14)	2020	Egypt	Double-blind RCT	90	Sex (total): 90 M/0 F (male only). Mean age (± SD) (years): Group I: 38.67±6.82; Group II: 37.63±8.77; Group III: 36.90±9.23	Group I: silodosin 8 mg. Group II: vardenafil 5 mg. Group III: silodosin 8 mg + vardenafil 5 mg. (Corticosteroid: no)	Max 4 weeks	Stone size (mm) (mean ± SD): diagnosis: CT/KUB; follow-up: USG; Group I (silodosin): 7.47±1.33; Group II (vardenafil): 7.07±1.23; Group III (combination): 7.50±1.28
Md Jawaid Rahman (16)	2018	India	RCT	120	Sex (total): 71 M/49 F. Mean age (± SD) (years): Group A: 38±10; Group B: 34±12; Group C: 35±10	Group A: tamsulosin 0.4 mg. Group B: silodosin 8 mg. Group C: silodosin 8 mg + tadalafil 5 mg. (Corticosteroid: no)	Max 4 weeks	Stone size (mm), mean (SD): diagnosis: USG/KUB; follow-up: USG/KUB; Group A (tamsulosin): 7.5 (1.20); Group B (silodosin): 7.4 (1.30); Group C (silodosin + tadalafil): 7.6(1.35)
Santosh Kuma (17)	2014	India	RCT	62	Sex (total): 44 M/18 F. Mean age (± SD) (years): Group A: 32.45±9.36; Group B: 35.23±13.54	Group A: tamsulosin 0.4 mg + prednisolone 5 mg. Group B: tamsulosin 0.4 mg + tadalafil 10 mg + prednisolone 5 mg. [Corticosteroid: yes (prednisolone)]	Max 6 weeks	Stone size (mm) (mean ± SD): diagnosis: NCCT; follow-up: X-ray/USG/NCCT; Group A (tamsulosin + prednisolone): 7.05±1.62; Group B (tamsulosin + tadalafil + prednisolone): 6.67±1.44
Diwas Gnyawali (18)	2020	Nepal	RCT	161	Sex (total): 108 M/53 F. Mean age (± SD) (years): Group A: 33.75±10.01; Group B: 32.85±10.36	Group A: tamsulosin 0.4 mg + tadalafil 10 mg. Group B: tamsulosin 0.4 mg. (Corticosteroid: no)	Max 3 weeks	Stone size (mm) (mean ± SD): diagnosis: CT/KUB; follow-up: USG; Group A (tamsulosin + tadalafil): 7.43 + 1.23; Group B (tamsulosin): 7.34±1.13

CT, computed tomography; F, female; KUB, kidney-ureter-bladder; M, male; Max, maximum; NCCT, non-contrast computed tomography; RCT, randomized controlled trial; SD, standard deviation; USG, ultrasonography.

Table 3. Summary of extracted clinical outcomes and adverse events across included studies.

Study	Interventions	Stone expulsion rate, n/N (%)	Stone expulsion time (days), mean ± SD	Pain episodes, mean ± SD	Analgesic use, mean ± SD	Adverse events [major reported events]
Muhammad Tayab 2022 (19)	Group A: tamsulosin 0.3 mg + tadalafil 8 mg. Group B: tamsulosin 0.3 mg. (Corticosteroid: no)	A: 63/80 (78.8%). B: 50/78 (64.1%)	A: 11.55±6.02. B: 16.10±5.25	A: 2.01±0.79. B: 2.33±0.66	A: 402±130 mg. B: 524±86 mg	A: backache [10], headache [9], dizziness [8], abnormal ejaculation [4]. B: headache [7], dizziness [6], backache [6], abnormal ejaculation [5]
Mohamed Mahmoud Dogha 2025 (13)	Group A: silodosin 8 mg. Group B: tamsulosin 0.4 mg. Group C: silodosin 8 mg + tadalafil 5 mg. Group D: tamsulosin 0.4 mg + tadalafil 5 mg. (Corticosteroid: no)	A: 32/45 (71.1%). B: 26/45 (57.8%). C: 41/45 (91.1%). D: 39/45 (86.7%)	A: 12.5±4.99. B: 14.6±5.34. C: 9.1±2.98. D: 10.1±4.36	A: 2.0±1.13. B: 3.0±1.50. C: 1.1±0.86. D: 1.5±1.34	A: 210.5±112.8 mg. B: 232.8±149.8 mg. C: 111.7±87.4 mg. D: 153.8±141.3 mg	A: retrograde ejaculation [9], headache [4]. B: retrograde ejaculation [6], headache [5]. C: retrograde ejaculation [7], headache [5]. D: retrograde ejaculation [5], headache [6]
Tamer Diab 2025 (12)	Group I: silodosin 8 mg. Group II: tadalafil 5 mg. Group III: silodosin 8 mg + tadalafil 5 mg. (Corticosteroid: no)	I: 30/42 (71.4%). II: 27/44 (61.4%). III: 37/42 (88.1%)	I: 14.1±4.0. II: 17.8±3.4. III: 10.4±3.5	I: 1.1±1.2. II: 1.4±1.2. III: 0.9±0.9	I: 508.9±480.5 mg. II: 520.4±460.6 mg. III: 276.8±271.4 mg	I: retrograde ejaculation [6], headache [4]. II: headache [6], backache [4]. III: retrograde ejaculation [7], headache [5]
Kumar Jayant 2014 (15)	Group A: tamsulosin 0.4 mg. Group B: tamsulosin 0.4 mg + tadalafil 10 mg. (Corticosteroid: no)	A: 80/122 (65.5%). B: 102/122 (83.6%)	A: 16.7±4.8. B: 14.9±4.4	A: 1.60±1.00. B: 0.45±0.68	A: 2.90±0.90 (times). B: 1.87±0.80 (times)	A: abnormal ejaculation [22], headache [14]. B: abnormal ejaculation [15], headache [18]
Mohamed Samir 2020 (14)	Group I: silodosin 8 mg. Group II: vardenafil 5 mg. Group III: silodosin 8 mg + vardenafil 5 mg. (Corticosteroid: no)	I: 23/30 (76.7%). II: 18/30 (60.0%). III: 27/30 (90.0%)	I: 12.50±1.66. II: 14.67±1.24. III: 11.23±3.14	I: 1.35±0.90 (hospital visits). II: 1.65±1.09 (hospital visits). III: 1.02±0.80 (hospital visits)	I: 613.4±483.6 mg. II: 716.9±685.3 mg. III: 313.6±285.5 mg	I: retrograde ejaculation [26]. II: headache [4], flushing [3]. III: retrograde ejaculation [26]
Md Jawaid Rahman 2018 (16)	Group A: tamsulosin 0.4 mg. Group B: silodosin 8 mg. Group C: silodosin 8 mg + tadalafil 5 mg. (Corticosteroid: no)	A: 23/40 (57.5%). B: 31/40 (77.5%). C: 36/40 (90.0%)	A: 21±4.6. B: 15±3.3. C: 12±2.2	A: 1.6±1.1. B: 0.8±0.06. C: 0.6±0.2	Not reported	A: retrograde ejaculation [5], headache [4], dizziness [4], orthostatic hypotension [3], backache [2]. B: retrograde ejaculation [6], headache [5], dizziness [3], backache [3], orthostatic hypotension [2]. C: retrograde ejaculation [6], headache [6], dizziness [4], backache [4], orthostatic hypotension [3]
Santosh Kumar 2014 (17)	Group A: tamsulosin 0.4 mg + prednisolone 5 mg. Group B: tamsulosin 0.4 mg + tadalafil 10 mg + prednisolone 5 mg. [Corticosteroid: yes (prednisolone)]	A: 23/31 (74.2%). B: 26/31 (83.9%)	A: 18.90±8.71. B: 15.15±5.40	A: 1.60±1.00. B: 0.45±0.68	A: 2.90±0.90 (times). B: 1.87±1.38 (times)	A: abnormal ejaculation [6], headache [4]. B: abnormal ejaculation [4], headache [5]
Diwas Gnyawali 2020 (18)	Group A: tamsulosin 0.4 mg + tadalafil 10 mg. Group B: tamsulosin 0.4 mg. (Corticosteroid: no)	A: 64/81 (79.0%). B: 50/80 (62.5%)	A: 11.6±6.1. B: 16.2±5.3	A: 2.02±0.80. B: 2.34±0.67	A: 403±131 mg. B: 526±86 mg	A: backache [11], headache [10], dizziness [9], abnormal ejaculation [5]. B: headache [8], backache [7], dizziness [7], abnormal ejaculation [6]

SD, standard deviation.

Risk of bias assessment

As shown in Figure 1, all studies were randomized. Regarding allocation concealment, four studies (13,16,18,19) were rated as unclear risk as they did not describe the methodology in detail. For blinding, three studies (12,14,15) were double-blind trials with a low risk of performance and detection bias. Conversely, three studies (16,18,19) were non-blinded (open-label) and judged to be at high risk. The remaining two studies (13,17) had an unclear risk of blinding. In terms of incomplete outcome data (attrition bias), three studies (13,16,17) were rated as low risk. However, two studies (12,14) were rated as high risk, and three studies (15,18,19) were rated as unclear risk. All eight studies fully reported their outcome indicators and were free of selective reporting bias. For other bias, seven studies were assessed as low risk, while only one study (19) was rated as unclear risk.

Meta-analysis

SER

The primary endpoint of all studies was the SER. The pooled meta-analysis showed (Figure 3A) that the SER in the combination therapy group was significantly higher than that in the group using only α-ARAs (RR =1.25, 95% CI: 1.17–1.35, P<0.001, I²=0%). Subgroup analysis stratified by the type of α-ARAs showed no significant difference in SER between the tamsulosin subgroup and the silodosin subgroup (Figure 3B). In our study, two studies (12,14), involvinga total of 146 participants compared the stone expulsion effects between the group using PDE5 inhibitor alone and the combination therapy group (RR =0.68, 95% CI: 0.56–0.84, P<0.001, I²=0%) (Figure 3C). The SER in the combination therapy group was significantly higher than that in the group using PDE5 inhibitor alone. Meanwhile, these two studies (12,14) also compared the stone expulsion effects between the group using PDE5 inhibitor alone (the dosage was 5 mg in both studies) and the group using only α-ARAs (the dosage was 8 mg in both studies) (RR =0.83, 95% CI: 0.66–1.04, P=0.10, I²=0%) (Figure 3D). The results showed that there was no significant difference in the stone expulsion effect between the group using PDE5 inhibitor alone and the group using only α-ARAs. In terms of absolute effects, the risk difference was 17.0%, translating to a number needed to treat (NNT) of approximately 6.

Figure 3.

Forest plots of the RR for SER. (A) Overall analysis of SER comparing combination therapy versus α-ARAs monotherapy. (B) Subgroup analysis of SER stratified by the type of α-ARAs (tamsulosin vs. silodosin). (C) Analysis of SER comparing PDE5 inhibitor monotherapy versus combination therapy. (D) Analysis of SER comparing PDE5 inhibitor monotherapy versus α-ARAs monotherapy. α-ARAs, α-adrenergic receptor antagonists; CI, confidence interval; M-H, Mantel-Haenszel; PDE5, phosphodiesterase-5; RR, risk ratio; SER, stone expulsion rate.

Stone expulsion time

Nine comparisons from eight studies summarized the average stone expulsion time. The experimental group received combination therapy, while the control group received only α-ARAs. The pooled meta-analysis (Figure 4A) showed that compared with using tamsulosin alone, the combination therapy significantly shortened the stone expulsion time (SMD =−0.73, 95% CI: −0.90 to −0.57, P<0.001, I²=36%). Subgroup analysis stratified by the type of α-ARAs showed no significant difference in stone expulsion time between the tamsulosin subgroup and the silodosin subgroup (Figure 4B).

Figure 4.

Forest plots of the SMD for SET. (A) Overall analysis of mean SET comparing combination therapy versus α-ARAs monotherapy. (B) Subgroup analysis of mean SET stratified by the type of α-ARAs (tamsulosin vs. silodosin). α-ARAs, α-adrenergic receptor antagonists; CI, confidence interval; IV, inverse variance; SD, standard deviation; SET, stone expulsion time; SMD, standardized mean difference.

Dosage of analgesics

Six comparisons from five studies (12-14,18,19) summarized the average dosage of analgesics used. The pooled meta-analysis showed (Figure 5A) that the dosage of analgesics used in the combination therapy group was significantly lower than that in the group using only α-ARAs (SMD =−0.89, 95% CI: −1.06 to −0.73, P<0.001, I²=38%). Subgroup analysis stratified by the type of α-ARAs showed no significant difference in analgesic dose reduction between the tamsulosin subgroup and the silodosin subgroup (Figure 5B).

Figure 5.

Forest plots of the SMD for total analgesic dose. (A) Overall analysis of the mean total analgesic dose comparing combination therapy versus α-ARAs monotherapy. (B) Subgroup analysis of the mean total analgesic dose stratified by the type of α-ARAs (tamsulosin vs. silodosin). α-ARAs, α-adrenergic receptor antagonists; CI, confidence interval; IV, inverse variance; SD, standard deviation; SMD, standardized mean difference.

Frequency of pain

Regarding pain episodes, all eight included studies consistently reported a reduction in the frequency of renal colic in the combination therapy group compared to monotherapy. However, the magnitude of this reduction varied substantially across trials, resulting in extreme statistical heterogeneity (I²=92%, P<0.001), as visually demonstrated in the unpooled forest plot (Figure 6). Extensive subgroup analyses based on drug type, follow-up duration, and study design failed to resolve this inconsistency. Consequently, we refrained from calculating a pooled quantitative estimate to avoid misleading conclusions. Instead, a narrative synthesis indicates that combination therapy is associated with fewer pain episodes across diverse clinical settings, although the precise effect size remains variable.

Figure 6.

Forest plot of mean pain episodes. Individual study results are displayed without a pooled overall estimate due to substantial statistical heterogeneity (I²=92%). CI, confidence interval; IV, inverse variance; SD, standard deviation.

Adverse reactions

Through our meta-analysis, we found that there was no significant difference in the incidence of most adverse reactions (hypotension, headache, abnormal ejaculation, dizziness) between the combination therapy and the monotherapy. For the outcome of back pain, it is noteworthy that no single included study individually reported a statistically significant difference between the combination and monotherapy groups. However, when we pooled the data from these seven studies (12,13,15-19) (Figure 7A), the meta-analysis indicated an association (OR =1.64, 95% CI: 1.07–2.50, P=0.02, I²=0%), suggesting a higher incidence in the combination therapy group.

Figure 7.

Forest plots of the OR for the adverse event of back pain. (A) Overall analysis of the incidence of back pain comparing combination therapy versus α-ARAs monotherapy. (B) Subgroup analysis of the incidence of back pain stratified by the type of α-ARAs (tamsulosin vs. silodosin). α-ARAs, α-adrenergic receptor antagonists; CI, confidence interval; M-H, Mantel-Haenszel; OR, odds ratio.

This finding must be interpreted with caution. As detailed in our Sensitivity analysis section, the association was not robust and lost statistical significance (P=0.06) upon the systematic exclusion of the study by Kumar Jayant (15).

The subgroup analysis (Figure 7B) suggested this non-robust effect was primarily driven by the tamsulosin subgroup (OR =1.66, 95% CI: 1.03–2.67, P=0.04), while the silodosin subgroup showed no significant difference (OR =1.56, 95% CI: 0.61–3.96, P=0.35). Given the non-robust nature of the overall finding, this subgroup result must also be interpreted with extreme caution.

Sensitivity analysis

A total of eight RCTs were included in this meta-analysis. Given the variable methodological quality identified in the risk of bias assessment (Figure 2) and the statistical heterogeneity present for some outcomes, a sensitivity analysis was conducted.

To investigate potential sources of heterogeneity and verify the robustness of our primary outcome (SER), we performed specific sensitivity analyses focusing on drug types and co-interventions. First, regarding drug type, the majority of included studies utilized tadalafil, with only one study [Samir et al. (14)] using vardenafil. We performed a sensitivity analysis by excluding this vardenafil study. The re-analysis of the remaining seven tadalafil-based studies showed that the SER remained significantly higher in the combination group (RR =1.26, 95% CI: 1.17–1.36, P<0.001, I²=0%), confirming that the efficacy is not dependent on a specific PDE5 inhibitor.

Second, to assess the influence of co-interventions, we excluded the study by Kumar et al. (17), which was the only trial that included corticosteroids (prednisolone) in the protocol. The results from the remaining studies confirmed that the benefit of combination therapy remained robust (RR =1.26, 95% CI: 1.17–1.36, P<0.001, I²=0%), indicating that the primary conclusion was not driven by corticosteroid use.

Furthermore, we performed a leave-one-out sensitivity analysis for adverse events. For the outcome of back pain incidence, the pooled result lost statistical significance (P=0.06) upon exclusion of the study by Kumar Jayant (15).

This finding indicates that the conclusion regarding increased back pain risk is not robust and is heavily influenced by this single study. For all other outcomes, the exclusion of any single study did not significantly alter the pooled effect estimates, confirming the robustness of these findings.

The certainty of the evidence for the main clinical outcomes was assessed using the GRADE framework. The detailed Summary of Findings (SoF), including the absolute and relative effects and the certainty ratings for SER, stone expulsion time, pain episodes, analgesic use, and back pain, is presented in Figure 8.

Figure 8.

GRADE SoF table. CI, confidence interval; PDE5, phosphodiesterase-5; RR, risk ratio; SD, standard deviation; SMD, standardised mean difference; SoF, Summary of Findings.

Discussion

Urolithiasis is one of the most common urinary system diseases globally, with a prevalence ranging from 1% to 13% in different regions (21). It is estimated that 13% of men and 7% of women will develop kidney stones, and the possibility of recurrence is high, with a recurrence rate of 50% within 5 years (22). The current recommendations of the European Association of Urology and the American Urological Association (5,6) for medical expulsive therapy (MET) suggest using α-ARAs as the best choice for stones between 5 and 10 mm stuck in the distal ureter. The National Institute for Health and Care Excellence Guideline and the Canadian Urological Association Guideline (23,24) recommend the application of α-ARAs for distal ureteral stones less than 10 mm in diameter in adults, children, and adolescents.α-ARAs significantly increase the spontaneous SER, shorten the stone expulsion time, reduce the frequency of pain attacks and the need for analgesics, and at the same time reduce the risk of hospitalization (evidence level 1a, recommendation grade A). Compared with calcium channel blockers, α-ARAs have more significant clinical treatment effects and lower risks, so they are recommended as the first-choice drugs for MET.

The earliest ureteral studies showed that both α-adrenergic receptors and β-adrenergic receptors play a role in the regulation of ureteral contractility in rats. Subsequent in vitro functional experiments using isolated porcine and human ureteral tissues further confirmed that the main response of the ureter to norepinephrine is contraction, which suggests that α1-adrenergic receptors dominate over β-adrenergic receptors in the ureteral smooth muscle (25). Ureteral stones are more likely to be retained in the distal ureter than in the upper ureter, and the maximum contraction induced by phenylephrine in the distal ureter is significantly greater than that in the upper ureter (26,27). The study by Sigala et al. showed that the density of α1-adrenergic receptors in the distal human ureter is significantly greater than that in the proximal ureter (28). Blockade of these receptors inhibits the basal tone of the ureteral smooth muscle and reduces the frequency and amplitude of norepinephrine-driven peristalsis, thereby effectively lowering intra-ureteral pressure (29). Therefore, for distal ureteral stones, α-ARAs can well promote the expulsion of stones from the distal ureter and have become the recommended treatment drugs for current MET.

Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) is an enzyme widely present in a variety of cells and tissues. Evidence from both animal and human studies confirms that PDE5 is highly expressed in ureteral smooth muscle, while soluble guanylate cyclase (sGC) is present in both the smooth muscle and urothelium (30). Furthermore, the presence of NOS-positive nerve fibers indicates a local regulatory mechanism (31). Functional studies on isolated human ureters demonstrate that NO donors induce dose-dependent smooth muscle relaxation, an effect significantly attenuated by the sGC inhibitor methylene blue and a protein kinase G (PKG) inhibitor, confirming the functional activity of this pathway in the human ureter (31,32). Inhibiting PDE5 can amplify the NO-cGMP pathway, resulting in the relaxation of vascular and non-vascular smooth muscles, such as ureteral smooth muscle (33,34). Some studies have shown that compared with placebo, PDE5 inhibitors can increase the expulsion rate of ureteral stones (35).

PDE5 inhibitors block the degradation of cGMP, leading to its intracellular accumulation and the subsequent activation of PKG.PKG promotes smooth muscle relaxation by reducing intracellular free Ca²⁺ concentration via inhibition of L-type Ca²⁺ channels and enhancement of Ca²⁺ reuptake and efflux, thereby decreasing myosin light chain kinase activity. Concurrently, PKG desensitizes the contractile apparatus to Ca²⁺ by activating myosin light chain phosphatase (36). Pharmacodynamically, these two drug classes are complementary: α-ARAs attenuate the primary adrenergic-driven contractile signals, while PDE5 inhibitors actively enhance the relaxation signal by amplifying cGMP signaling. This dual action leads to a collective reduction in ureteral spasm and intra-ureteral pressure, making it more difficult for the smooth muscle to enter a state of high-frequency, high-amplitude contraction. This synergistically facilitates distal stone expulsion and provides more effective relief from renal colic.

There is no obvious difference in the SER when using PDE5 inhibitors or α-ARAs alone. In a single-center prospective randomized study (37), the stone expulsion effects of PDE5 inhibitors (tadalafil) and α-ARAs (tamsulosin) were compared. The results showed that the SER in the PDE5 inhibitor group was 84%, and that in the α1-adrenergic receptor antagonists group was 68% (P=0.013). The SER in the PDE5 inhibitor group was better than that in the α-ARA group. In another single-center prospective randomized study (38), under the same drugs and the same dosage, the results showed that there was no obvious difference in the SER between the PDE5 inhibitor group and the α-ARAs group (69.35% vs. 73.77%, P=0.69). In the meta-analysis of the two studies we included, there was no obvious difference in the SER between the PDE5 inhibitor group and the α-ARAs group (60.8% vs. 73.6%, P=0.1). To broaden the scope beyond tamsulosin, recent comprehensive meta-analyses have also compared silodosin directly with tadalafil. For instance, a 2025 meta-analysis by Ebrahimpour et al. (39) pooling data from 546 patients found no significant difference between silodosin and tadalafil regarding SER (OR =1.19) or expulsion time. Similarly, another updated meta-analysis by Abdalaziz et al. (40) corroborated that the pooled results initially showed no significant difference in expulsion rates or times between silodosin and tadalafil monotherapies, although silodosin might offer slight advantages after adjusting for heterogeneity. These findings collectively reinforce that while various α-ARAs and PDE5 inhibitors are individually effective, neither monotherapy class is overwhelmingly superior, highlighting the necessity to explore their synergistic combination. Currently, due to long-term safety, more sufficient clinical data, and lower prices, α-ARAs are the first-choice recommended drugs for the treatment of distal ureteral stones. It is worth exploring the treatment effects of their combination with PDE5 inhibitors on ureteral stones through different mechanisms.

The combination of α-ARAs and PDE5 inhibitors significantly increases the SER. In our study, eight studies were included to compare the SERs between the α1-adrenergic receptor antagonists group and the combination therapy group, which were 84.3% (435/516) vs. 67.3% (345/513). Two studies compared the stone expulsion effects between the group using PDE5 inhibitor alone and the combination therapy group, and the SERs were 60.8% vs. 88.9%. Both results suggested that the combination therapy had good efficacy, which was consistent with the results of the current known single-center prospective randomized studies.

In a meta-analysis including four studies by Belkovsky et al. (9), there was no obvious difference in the frequency of pain (OR =0.20, 95% CI: −0.38 to 0.78; P=0.51, I²=94%) and the average stone expulsion time (MD=1.07, 95%CI: −0.25 to 2.39; P=0.11, I²=84%) between the group using tamsulosin alone and the group using tadalafil alone. In our study, compared with α-ARAs monotherapy, the combination therapy group significantly shortened the average stone expulsion time. However, for the outcome of frequency of pain, our analysis revealed substantial and persistent statistical heterogeneity (I²=94%, P<0.001). Extensive subgroup analyses stratified by study blinding, follow-up duration, and pain definition failed to resolve this, with high heterogeneity persisting within all subgroups. This indicates the included studies are too clinically and methodologically dissimilar to be meaningfully pooled.

The combination of α-ARAs and PDE5 inhibitors may cause additional side effects. When we analyzed the side effects between the group using α-ARAs alone and the combination therapy group, we made new discoveries. There was no obvious difference in the incidence of dizziness, hypotension, and headache between the two groups, which was consistent with the results of the included studies. In the eight included studies, each study showed that there was no obvious difference in the incidence of back pain between the group using α-ARAs alone and the combination therapy group. However, when we conducted a meta-analysis on the eight studies, the combination therapy group was more likely to have back pain than the monotherapy group. Subgroup analysis suggested that combination therapy with tamsulosin might be associated with an increased risk of back pain. However, this finding must be interpreted with caution. The statistical significance of this association disappeared after excluding the study by Kumar Jayant (15) (P=0.06), indicating that the conclusion lacks robustness and is susceptible to the influence of a single study.

Nonetheless, potential pharmacological mechanisms for this association exist. Tadalafil, the most frequently used PDE5 inhibitor in the combination regimens in this analysis, has well-known side effects of myalgia and back pain. This is primarily attributed to its cross-inhibition of the PDE11 enzyme (41). PDE11 is highly expressed in skeletal muscle, and the catalytic site of tadalafil shares structural similarity with that of PDE11 (42).

Back pain was explicitly listed in the adverse event table of a multicenter, placebo-controlled Phase III trial of tamsulosin (43), with reported incidences of approximately 5% (0.4 mg), 9% (0.8 mg), and 7% (placebo). Therefore, the increased incidence observed in the combination group may reflect an additive reporting of side effects from both drugs. Finally, back pain itself is a challenging outcome measure in patients with ureteral stones, as phenotypic overlap may exist—that is, the reported pain may partially represent residual renal colic or myofascial pain rather than a pure drug-induced adverse event.

In clinical practice, if patients are sensitive to tadalafil-related myalgia during combination therapy, treatment optimization strategies may be considered. For example, switching to a PDE5 inhibitor with lower affinity for PDE11 (41), or utilizing the lowest effective dose of tadalafil, administered in the evening, and supplemented with short-term symptomatic analgesics.

Due to the limited number of included studies (n<10), we did not perform funnel plot analysis or Egger’s test to evaluate publication bias, as these methods lack sufficient statistical power to reliably detect asymmetry when fewer than 10 studies are available according to the Cochrane Handbook guidelines.

Limitations

Our study has several limitations that merit consideration. First, the quality of evidence is constrained by the design of the included studies. The majority of the trials were small-sample, single-center studies. Notably, some trials employed an open-label design or lacked detailed descriptions of allocation concealment methods, which may introduce potential performance and selection biases. Second, there was clinical heterogeneity across the included protocols. Specifically, variability existed in drug dosages, treatment durations, and the use of co-interventions (such as corticosteroids), all of which could influence efficacy outcomes and adverse event rates. Additionally, some studies did not explicitly document baseline details like the duration of renal colic, limiting our ability to perform specific subgroup analyses. Third, regarding outcome assessment, we observed high statistical heterogeneity for pain episodes. Due to substantial variations in pain assessment scales and reporting methods, we refrained from performing a quantitative synthesis for this outcome to avoid misleading pooled estimates. Finally, we were unable to formally assess potential publication bias using funnel plots or Egger’s regression test because the number of included studies was small (n<10). Consequently, the potential for publication bias cannot be completely excluded. Therefore, large-scale, multi-center, double-blind, placebo-controlled trials are strictly needed for further verification.

Conclusions

For single distal ureteral stones less than 10 mm in diameter, the heterogeneous combination strategies utilizing α-ARAs and PDE5 inhibitors can significantly increase the SER, reduce the stone expulsion time, and lower the dosage of analgesics used. The pooled analysis for pain episodes was limited by substantial, unexplained heterogeneity and could not be confirmed as a definitive benefit. Furthermore, an association with a higher risk of back pain was observed; however, this finding must be interpreted with caution.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.