Introduction
Endoscopic management of ureteral calculi has evolved into the standard of care for obstructive urolithiasis. However, a fundamental challenge persists: gaining atraumatic access through the lower ureteric orifice (LUO), particularly when using large-caliber ureteroscopes. Excessive ureteral resistance at the orifice not only prolongs operative time but also increases the risk of mucosal injury, perforation, and postoperative stricture formation. Thus, pharmacologic facilitation of ureteral smooth muscle relaxation before ureteroscopy has become an increasingly appealing concept in urologic practice.
The pharmacologic approach aims to exploit alpha-adrenergic blockade and nitric oxide–mediated smooth muscle relaxation to reduce ureteral tone. Drugs such as tamsulosin, an α1-receptor antagonist, and tadalafil, a phosphodiesterase-5 (PDE5) inhibitor, have demonstrated potential for easing stone passage in medical expulsive therapy. Their possible use in pre-procedural ureteral dilation represents a logical extension of this mechanism. Moreover, deflazacort, a glucocorticoid with potent anti-inflammatory activity, may reduce periorificial edema, further aiding negotiation.
The present clinical trial compared these pharmacologic regimens — individually and in combination — to determine their relative effectiveness and safety in improving LUO negotiation during ureteroscopy for lower ureteral stones. The findings not only provide practical guidance for surgical preparation but also illuminate the nuanced interplay between ureteral physiology and pharmacodynamics.
Study Design and Methodology
This prospective, randomized, single-center study enrolled 120 patients scheduled for ureteroscopic removal of lower ureteric calculi measuring 8–12 mm in diameter. All participants were adults with normal renal function and no history of ureteral stricture or prior endoscopic intervention. The patients were randomly assigned into four equal groups (n = 30):
- Group A: Tamsulosin 0.4 mg once daily
- Group B: Tadalafil 10 mg once daily
- Group C: Combination of tamsulosin 0.4 mg + tadalafil 10 mg daily
- Group D: Deflazacort 6 mg twice daily
All medications were administered for seven days prior to surgery. No pre-stenting was performed. Ureteroscopy was carried out using a 9.8 Fr semirigid ureteroscope, introduced without prior balloon dilation or guidewire pre-passage beyond the orifice.
The primary endpoint was the ease of LUO negotiation, graded on a 3-point scale:
- Grade I – Easy negotiation
- Grade II – Moderate resistance
- Grade III – Significant resistance or failure to negotiate without dilation
Secondary outcomes included:
- Ureteral injury rate (graded by the Traxer–Smith classification)
- Need for mechanical dilation
- Operative time
- Postoperative complications
The trial’s design ensured objectivity through blinded evaluation of intraoperative findings and postoperative outcomes by independent observers.
Results: The Quantitative Core
The study yielded a clear pharmacologic hierarchy in facilitating LUO negotiation.
Ease of LUO Negotiation:
- Tadalafil (Group B): Easy in 83.3% of cases
- Tamsulosin (Group A): Easy in 73.3%
- Combination (Group C): Easy in 90% — the best outcome overall
- Deflazacort (Group D): Easy in only 43.3% of cases
These differences were statistically significant (p < 0.001). Notably, only 10% of patients in the combination group required auxiliary mechanical dilation, compared to 26.6% in the tamsulosin group and 36.6% in the deflazacort group.
Operative Time:
The mean time for LUO negotiation and complete stone clearance was shortest in the combination group (8.2 ± 2.1 minutes) and longest in the deflazacort group (12.8 ± 3.4 minutes, p < 0.05).
Ureteral Injury:
Minor mucosal injury (Grade 1) occurred in 6.6% of tadalafil-treated cases, 10% of tamsulosin cases, and 20% of deflazacort cases. None of the combination-treated patients experienced clinically significant trauma.
These numerical findings confirm that PDE5 inhibition alone is effective, but synergistic blockade of α-adrenergic receptors further optimizes ureteric smooth muscle relaxation.
Pharmacologic Basis of Ureteric Relaxation
The lower ureteric orifice is a dynamic structure rich in α1A-adrenergic receptors and PDE5 enzyme activity. Both systems regulate smooth muscle tone through calcium-dependent pathways that modulate intracellular cGMP and cAMP concentrations.
Tamsulosin, by selectively antagonizing α1A receptors, inhibits noradrenaline-induced contraction of distal ureteral smooth muscle. The result is a passive dilation that reduces peristaltic resistance and facilitates endoscopic advancement.
Tadalafil, a PDE5 inhibitor traditionally used for erectile dysfunction, augments nitric oxide–mediated relaxation by preventing cGMP degradation. Unlike tamsulosin, tadalafil also enhances endothelial vasodilation and microvascular perfusion, potentially reducing ischemic spasm at the orifice.
When combined, the two drugs target distinct but complementary molecular pathways:
- Tamsulosin decreases baseline tone.
- Tadalafil sustains active smooth muscle relaxation and improves vascular compliance.
This mechanistic synergy explains the superior ease of orifice entry and reduced trauma observed in the combination arm.
Deflazacort: Anti-Inflammatory but Functionally Limited
Deflazacort’s inclusion reflects an interest in mitigating edema and inflammatory stiffness around the orifice, which can follow chronic stone irritation. Although theoretically beneficial, the results demonstrated that anti-inflammatory reduction alone does not equate to functional relaxation of the ureteral sphincteric segment.
The corticosteroid may have slightly improved mucosal pliability, but it failed to match the efficacy of adrenergic and PDE5 blockade. Moreover, while no systemic corticosteroid complications were observed in this short course, deflazacort did not influence operative ease, reinforcing that mechanical obstruction in the ureter is primarily myogenic rather than edematous in origin.
Clinical Significance of the Findings
The findings redefine preoperative optimization in ureteroscopy for distal calculi. Traditionally, urologists relied on mechanical dilation or smaller scopes to negotiate difficult orifices, but both strategies carry drawbacks. Mechanical dilation increases trauma risk, and smaller scopes limit visualization and instrument passage.
Pharmacologic relaxation with agents such as tadalafil and tamsulosin presents a minimally invasive, reversible, and safe alternative. In the combination arm, 90% of procedures required no dilation, effectively reducing procedural trauma and postoperative pain.
This has multiple downstream benefits:
- Shorter anesthesia and operative time.
- Decreased postoperative hematuria and edema.
- Improved stone-free rates at first session.
- Faster recovery and discharge.
From a cost perspective, the low expense of oral tadalafil and tamsulosin makes preoperative administration highly accessible, particularly in resource-limited environments where sophisticated dilation devices are scarce.
Comparative Literature and Context
Previous investigations have explored medical expulsive therapy (MET) using tamsulosin and tadalafil for spontaneous stone passage. The present study extends these principles to the operative arena.
In Dell’Atti et al. (2014), tadalafil 5 mg daily improved distal ureteric stone expulsion rates compared with placebo, highlighting its direct influence on ureteral motility. Similarly, Porpiglia et al. (2010) demonstrated that α-blockade facilitated faster stone clearance with fewer colic episodes.
However, no prior trial directly compared these agents as pre-endoscopic relaxants under controlled conditions. The African Journal of Urology study thus fills a critical gap, providing empirical support for perioperative pharmacologic ureteral preparation — a concept analogous to bowel preparation in gastrointestinal surgery.
Notably, the combination regimen’s superiority aligns with the mechanistic hypothesis: dual modulation of adrenergic and nitric oxide pathways yields additive relaxation, supporting multimodal pharmacotherapy in endourologic optimization.
Safety and Tolerability Profile
A major advantage of this pharmacologic strategy lies in its safety. Across all treatment arms, no major adverse events were reported. Minor transient effects included:
- Headache (7% in tadalafil groups)
- Nasal congestion (5% in tamsulosin groups)
- Mild dyspepsia (3% overall)
No patients discontinued therapy. Blood pressure remained stable, and no episodes of intraoperative hypotension or arrhythmia occurred. Laboratory evaluations revealed no hepatotoxicity or electrolyte disturbances.
This excellent safety record underscores the feasibility of routine short-term pre-procedural use in surgical patients, even among those with cardiovascular risk factors — provided that standard contraindications to PDE5 inhibitors are observed.
Implications for Endourologic Practice
The implications extend beyond distal ureteric procedures. The concept of pharmacologic ureteric preparation may improve outcomes in:
- Difficult proximal stone retrievals
- Rigid scope advancement in narrow ureters
- Pediatric or female patients with small-caliber orifices
- Reducing the need for pre-stenting
Moreover, adopting this approach enhances surgeon comfort and confidence, allowing smoother scope navigation and reducing the cognitive stress associated with resistance during entry — a factor often underestimated in surgical ergonomics.
For hospitals, reduced dilation equipment usage translates into lower costs and faster case turnover, a significant advantage in high-volume urology centers.
Limitations and Future Perspectives
While compelling, this trial’s scope was limited by its sample size (n=120) and single-center design. Larger multicentric studies could validate generalizability across ethnic and anatomical variations. Furthermore, all participants had lower ureteral stones; the drug’s impact on mid- or upper-ureteral access remains untested.
Pharmacokinetic optimization is another avenue for exploration. Since tadalafil’s half-life is 17.5 hours, future protocols might evaluate shorter pre-treatment durations or lower dosages. Additionally, incorporating imaging-based quantification (e.g., high-resolution ultrasound of ureteral peristalsis) could yield objective biomarkers for ureteric relaxation.
Finally, while no adverse hemodynamic effects were seen, caution remains prudent in patients on nitrates or potent antihypertensives, given known pharmacologic interactions.
Broader Pharmacologic Insights
This study highlights an evolving therapeutic paradigm: using erectogenic agents for urological tissue modulation. PDE5 inhibitors have transcended their original domain, demonstrating benefits in benign prostatic hyperplasia, renal ischemia, and even pulmonary hypertension through their endothelial and smooth muscle effects.
In the ureter, tadalafil’s vasodilatory influence likely enhances mucosal perfusion and oxygenation, mitigating ischemia-induced hyperreactivity. Tamsulosin’s action complements this by reducing baseline sympathetic tone, an important factor in ureteric hyperperistalsis.
Thus, the data provide yet another example of how pharmacologic repurposing can optimize surgical efficiency without invasive intervention — an approach that aligns perfectly with modern principles of minimally invasive, physiology-guided medicine.
Conclusion
This prospective randomized study establishes a clear pharmacologic hierarchy for pre-procedural ureteric relaxation in ureteroscopy. The combination of tamsulosin (0.4 mg daily) and tadalafil (10 mg daily) administered for seven days before surgery offers the greatest ease of LUO negotiation, shortest operative time, and lowest risk of mucosal injury compared to either monotherapy or anti-inflammatory treatment alone.
The results confirm that functional relaxation, rather than mere reduction of inflammation, is the key determinant of successful ureteric access. Both tamsulosin and tadalafil contribute through complementary molecular mechanisms, and their combined effect redefines the concept of “pharmacologic ureteral dilation.”
Given its low cost, safety, and significant procedural advantages, this regimen deserves consideration as standard pre-operative preparation in all patients undergoing ureteroscopy for lower ureteric stones.
As the field of endourology continues to refine minimally invasive techniques, the integration of pharmacologic facilitation represents an elegant example of how precision medicine can enhance even the most routine surgical procedures.
FAQ
1. How long should tadalafil and tamsulosin be taken before ureteroscopy?
The study protocol used a 7-day pre-treatment regimen. This duration appears sufficient to achieve optimal ureteric relaxation, but shorter courses (3–5 days) may still provide benefit pending further research.
2. Is combination therapy safe for all patients?
Generally yes, but caution is advised in men using nitrates, potent antihypertensives, or with severe hepatic impairment. Short-term use under medical supervision is well tolerated.
3. Can these drugs replace mechanical dilation altogether?
In most cases of distal ureteral stones, yes. The combination significantly reduces or eliminates the need for dilation, minimizing trauma and shortening operative time. However, mechanical dilation may still be necessary in rare cases of congenital or fibrotic narrowing.
Reference:
El-Sheemy M.S. et al. (2018). Comparison of safety and efficacy of tamsulosin, tadalafil, combinations and deflazacort in lower ureteric orifice negotiation by large size ureteroscope prior to intracorporeal lithotripsy. African Journal of Urology, 24(2), 112–119.
