Patients with urinary tract stones account for 20% of urology inpatients [1]. Urinary tract stones remain common, affecting up to 5% of people worldwide [2]. The prevalence of urinary tract stone disease in Korea is steadily rising.

The location (upper, mid, and lower) and size of the stone as well as stone composition and complications are determining factors in the treatment of urinary stones. Treatments are divided into three broad groups: 1) observation and medical therapy, 2) shock wave lithotripsy (SWL) and ureteroscopy, and 3) open surgery, laparoscopic stone removal, or percutaneous antegrade ureteroscopy. Urolithiasis treatment has been shifting to less invasive therapies such as SWL or ureteroscopy. Despite improved treatment, however, the rate of recurrence of urinary tract stones remains high. Tomson [3] reported a 67% and 75% recurrence of urolithiasis within 9 years and 25 years, respectively. Fifty percent of those with urinary tract stones will experience one or more recurrences. Therefore, the initial treatment is very important; no remaining stones should be present and ureteral injury, sepsis, and infection should not occur as a result of the intervention.

For stones 5 to 10 mm in size, analysis of groups yielded an estimate that 47% would pass spontaneously [4]. Various studies of efficient stone expulsion have been done for increasing the stone expulsion rate. The 2007 Guideline for Management of Ureteral Calculi of The American Urological Association (AUA) and the European Association of Urology (EAU) guideline recommend watchful waiting with medical treatment for patients with a stone <10 mm in diameter and well-controlled pain [4].

Currently, non-selective α-blockers such as alfuzosin (10 mg daily) and doxazosin (4 mg daily) and α-1a and α-1d selective α-blockers such as tamsulosin (0.4 mg daily) are used for the spontaneous expulsion of lower ureteral stones or to facilitate stone removal after SWL [5-7]. In Korea and Japan, only tamsulosin 0.2 mg is produced and the administration of the total daily dose of tamsulosin is achieved by the use of two doses of 0.2 mg. This regimen is more onerous and expensive than the use of a single 0.2-mg daily dose and adverse effects such as retrograde ejaculation can be increased. Adverse effects such as dizziness, orthostatic hypotension, headache, and fatigue may occur by taking nonselective α-blockers.

Presently, we compared the impact of 0.2 mg tamsulosin with that of 0.4 mg tamsulosin and 10 mg alfuzosin in patients with lower ureteral stones of 4 to 10 mm in diameter and with controlled pain, with the aim of clarifying the treatment regimen that is superior for spontaneous stone expulsion.

Various treatment options are considered for the management of lower ureteral stones, including open ureterolithotomy, ureteroscopic lithotripsy (URS), and SWL. According to the 2007 Guideline for the Management of Ureteral Calculi of the AUA and the EAU guideline, URS stone-free rates were significantly better than SWL rates for distal ureteral stones ≤10 mm and >10 mm [4]. The availability of this modality and physician experience were considered. Complications such as sepsis, stricture, ureteral injury, and urinary tract infection are the most relevant complications.

Spontaneous stone passage was often reported without active treatment including URS and SWL. One study reported spontaneous expulsion in 25 to 53% of cases for distal ureteral stones 5 to 10 mm in diameter [10]. Another study reported spontaneous passage of 68% of stones <5 mm in diameter and 47% of stones 5 to 10 mm in diameter [5]. Ureteric calculi more than 10 mm in diameter should be removed by emergency URS or medical expulsion treatment (MET), because large calculi tend to impact in the ureter and are unlikely to migrate in the distal region [11]. More distal stones are more likely to pass spontaneously, and Miller and Kane [12] reported that the interval to stone passage was highly variable and dependent on stone size and location. The hazard of expulsion at any time was 3-fold higher for stones located at the ureterovesical junction than for those in the distal part of the ureter [13]. Accordingly, the most important factors in predicting the likelihood of spontaneous stone expulsion are stone size and stone location [14].

The ureter demonstrates two continuous thin muscle layers with a loosely spiraled internal layer and a more tightly spiraled external layer. In the lower third of the ureter, a third outer longitudinal layer is present. The lower ureter is composed of transitional epithelium, a connective tissue layer, and three layers of smooth muscle [15]. Ureteral peristalsis is initiated by spontaneous activity of the renal pelvis pacemaker cell and is essentially regulated by the myogenic mechanism and neurogenic factors; thereafter, electrical and mechanical activities are conducted to inactive distal regions [16]. The α-adrenoceptor pathway was first described in the human ureter in the 1970s [17]. Activation of α1-adrenoceptors leads to ureteral contraction via activation of phospholipase C, which in turn leads to the formation of second messengers (inositol triphosphanate [IP3] and diacylglycerol [DAG]). IP3 is involved in the mobilization of calcium from the sarcoplasmic reticulum, whereas DAG increases calcium influx across the cell membrane via the activation of protein kinase C [18]. Thus, the histologic characteristics of the three smooth muscle layers in the lower ureter and the more dense innervation of the lower ureter than the upper and mid ureter have become subjects of research interest.

The stimulation of the α1-receptors in the incomplete or complete ureteral obstruction by ureteral calculi increases the force of ureteral contraction and the frequency of ureteral peristalsis. Thus, a blockade of α1-receptors inhibits basal tone, reduces peristaltic amplitude and frequency, and decreases intra-luminal pressure. α-blockers also induce an increase in the intra-ureteral pressure gradient around the stones that helps in stone expulsion [19]. Patients who elect for an attempt at MET, such as the use of an α-blocker, should have well-controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve. The patients should be followed with periodic imaging studies to monitor stone position and to assess for hydronephrosis or severe adverse effects. If the outcome of this treatment is not satisfactory, active stone removal modalities like URS or SWL should be required [4]. Follow-up at 7, 14, 21, and 28 days with blood test, urine test, and radiologic test should be practiced for such serious conditions. It is very important that the patient be advised of the attendant risk including the associated side effects of treatment modalities like URS, SWL, and MET, and that MET should be performed.

Medical treatments using nonselective α-blockers for spontaneous stone expulsion have been reported. Agrawal et al. [20] reported that for stones ≤ 1 cm, 10 mg alfuzosin results in a 35% increase in the stone expulsion rate, decreased expulsion time, and good control of colic pain compared with a control group. Pedro et al. [5] reported good pain control and stone expulsion time compared with a control group by using alfuzosin but found no significant difference in the stone expulsion rate between the afluzosin and control groups (73.5% vs. 77.1%). In the latter study, it is possible that the high rate of stone expulsion in the control group was unrelated to the effect of alfuzosin but rather reflected the small size of the stones in both groups (4.08 mm and 3.83 mm). In our study, the alfuzosin group displayed a 27.9% increased stone expulsion rate compared with the control group (p=0.026).

The α-1d receptor has the highest density in the distal ureter [18]. Tamsulosin, which is a selective α-1a and α-1d blocker, is a commonly used α-blocker for the medical treatment of ureteric stones. Al-Ansari et al. [21] reported that 0.4 mg tamsulosin produced a 26% increased stone expulsion rate and decreased stone expulsion time. Resim et al. [7] reported that the same dose of tamsulosin produced an insignificantly increased rate of stone expulsion (13.3%) and decreased colic episodes and pain. Hermanns et al. [13] reported no significant difference in the expulsion rate between the group using 0.4 mg tamsulosin and the control group (86.7% vs. 88.9%, respectively). However, these results involved small-sized stones (mean, 3.8 mm) in both groups, similar to the study of Pedro et al. [5].

In Korea and Japan, 0.2 mg tamsulosin is taken orally twice daily to achieve the affects attributed to 0.4 mg tamsulosin. This regimen is expensive and onerous and adverse effects such as retrograde ejaculation and fatigue can be increased. In our country, 0.2 mg tamsulosin is used for control of symptoms of benign prostatic hyperplasia; because the α-1d receptor is more dense in the lower ureter, we used the same dose of tamsulosin for MET. Yoon et al. [22] reported that the use of 0.2 mg tamsulosin produced a 25.7% increased stone expulsion rate and decreased expulsion time for 3 days for stones <10 mm in diameter. In two other studies, 0.2 mg tamsulosin resulted in increased stone migration and an increased stone expulsion rate [23,24]. However, studies that have compared tamsulosin 0.2 mg and 0.4 mg are not much more prevalent than those that have compared a nonselective α-blocker and tamsulosin. In particular, to our knowledge, the present study is the first direct comparison of 10 mg alfuzosin, 0.2 mg tamsulosin, and 0.4 mg tamsulosin in the management of lower ureteral calculi.

Comparison between the two tamsulosin doses and the 10-mg alfuzosin dose revealed no significant differences in expulsion rate or expulsion time. The expulsion time observed in this study was shorter than reported previously [25]. The higher expulsion rate observed with 0.2 mg tamsulosin compared with 0.4 mg tamsulosin was likely not a statistical error caused by the small numbers of subjects, but rather that the lower dose of tamsulosin was sufficient to lower ureteral peristalsis.

Similar to a previous study [26], all groups treated in this study with 0.2 mg tamsulosin, 0.4 mg tamsulosin, and 10 mg alfuzosin displayed no differences in postural hypotension. There were also no differences in dizziness, headache, and fatigue in these groups, which is also consistent with other studies [7,18,20]. Although tamsulosin has been linked to a higher incidence of retrograde ejaculation than the non-selective α-blocker alfuzosin [20], in our study, there was no significant difference in abnormal ejaculation between the groups. Whether the current result is real is debatable. The short-term nature of this study and the less frequent sexual behavior of urinary stone patients may have confounded the findings.

When a single ureteral stone remains after 28 days of medical treatment, URS, SWL, and a second cycle of MET can be used for stone removal. A second cycle of tamsulosin therapy in nonresponders to a first cycle of MET may not significantly improve the expulsion rate [27]. Hubner et al. [28] reported that a maximum observation period of 30 days was chosen because a longer period could increase the complication rate by 20%. Thus, we advocate the need for aggressive stone removal such as URS or SWL when the first cycle of MET has failed.

The use of tamsulosin doses of 0.2 mg and 0.4 mg and of 10 mg alfuzosin for MET of single lower ureteral stones of 4 to 10 mm in diameter proved to be safe and effective as demonstrated by the increased stone expulsion rate, decreased expulsion time, and no significantly different adverse effects. We confirm that a first cycle of MET with 0.2 mg tamsulosin is safe and effective and can be considered as an option in the management of a single lower ureteral stone.