The primary benefit of conservative approach in the management of ureteral calculi is minimal patient morbidity. Conservative medical treatment is usually indicated in the treatment of uncomplicated distal ureteral stones of 6–10 mm size as these stones have lower chances to pass spontaneously .
A great advance in the MET has been achieved with the use of α-1 adrenoreceptor antagonists to treat these stones by accelerating stone passage through inducing relaxation of distal ureteral smooth muscles . The α-1 adrenoreceptor antagonists act by inhibiting basal muscular tone, uncoordinated hyperperistaltic wave frequency and ureteral contractions of distal ureter leading to relaxation of ureteral smooth muscles with subsequent ureteral lumen dilatation which results in increase in the rate of stone expulsion .
Recently, PDE5 inhibitors were reported to act on the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in the smooth muscles, resulting in accumulation of cGMP, resulting in ureteral smooth muscle relaxation. So, PDE5 inhibitors are potentially able to facilitate stone expulsion . Despite having a well-established role in erectile dysfunction (ED) and benign prostatic hyperplasia (BPH), the use of PDE5 inhibitor for MET is in the preliminary stage.
In our study, we found that the stone expulsion rate was significantly higher in combination than silodosin and vardenafil groups (90.0%, 76.7% and 60.0%, respectively) (P = 0.025). Like our results, Girish et al.  reported that there was a higher expulsion rate 76% in combination therapy group compared to 73% in tadalafil group and 70% in tamsulosin group. There was an increase in expulsion rate in patients with combination therapy, though statistical significance could not be demonstrated. Kumar et al.  reported that the stone expulsion rates for tamsulosin, silodosin and tadalafil were 64.4%, 83.3% and 66.7%, respectively, but there was no significant difference between the tamsulosin and tadalafil groups (P = 0.875). Abhishek et al.  reported that the stone expulsion rate was 58% for placebo group, 80% for tadalafil group and 74% for tamsulosin group. Tadalafil was superior to placebo in stone expulsion rate (P = 0.017).
The reason for a higher stone expulsion rate in combination group can be explained by the fact the combination of vardenafil and silodosin with different mechanisms of action. Silodosin acts as α-1A adrenoceptor blocker, whereas vardenafil acts as PDE5 inhibitor, and thus, the combination of the two drugs may further help in increase in stone expulsion .
In this study, we found that the mean stone expulsion time was significantly shorter in combination than silodosin and vardenafil groups (11.23 ± 3.14, 12.50 ± 1.66 and 14.67 ± 1.24 days, respectively, P < 0.01). Similarly, Girish et al.  concluded that the time to expulsion was lesser in combination therapy compared to tamsulosin and tadalafil groups, but this difference was not statistically significant (3.61, 4.05 and 4.14 days, respectively, P = 0.545). Kc et al.  showed that the mean stone expulsion time was lower in tadalafil (8.08 ± 3.3 days) than in tamsulosin groups (9.64 ± 3.8 days), but also this difference was not statistically significant (P = 0.094). However, Goyal et al.  reported that the mean expulsion time was lower for tamsulosin (9.38 ± 6.66 days) than for tadalafil groups (9.61 ± 7.47 days), but this difference was not significant (P = 0.78). In contrast, Puvvada et al.  reported that the mean time for stone expulsion in tadalafil was 14.7 ± 3.8 days and in tamsulosin groups was 16.8 ± 4.5 days. The time was significantly shorter in tadalafil group than tamsulosin group (P = 0.0021).
We found that the number of hospital visits for pain was statistically significant between groups (silodosin = 1.35 ± 0.9, vardenafil = 1.65 ± 1.09 and combination groups = 1.02 ± 0.80) (P = 0.038) and the amount of analgesic of intake for pain was significantly the least in combination (313.6 ± 2.85.5), followed by silodosin (613.44 ± 483.62), and then vardenafil groups (716.97 ± 685.3 mg of diclofenac sodium) (P = 0.008). Similarly, Rahman MJ et al.  found that silodosin plus tadalafil had significantly fewer pain episodes than silodosin and tadalafil alone (P < 0.001). Also, Jayant et al.  showed significantly fewer episodes of pain with tadalafil plus tamsulosin as compared to tamsulosin alone. This may be explained by the different mechanism of action of the two drugs. Silodosin blocks the C fibers, and tadalafil acts through decreasing the frequency and amplitude of ureteric phasic contractions and decreases the intra-luminal ureteric pressure, and so reduces pain episodes .
In our study, we found that there were no significant differences among the studied groups regarding headache, dizziness and orthostatic hypotension (P > 0.05). This can be explained by the young age of the studied population. However, there was a highly significant difference among the studied groups regarding retrograde ejaculation (silodosin and combination = 86.7% vs vardenafil groups = 0.0%) (P < 0.05) and the increased erection was significantly higher in group III (vardenafil plus silodosin) (0.010). This can be an advantage in patients with lower ureteric stones and ED. However, all these side effects were mild and well tolerated. No patients were excluded from the study because of occurrence of side effects. Similarly, Girish et al.  reported that there were no serious adverse effects noted and Goyal et al.  showed that no statistical difference was detected for adverse drug effects except for retrograde ejaculation, which was significantly higher in tamsulosin group (P < 0.001). Again, Kc et al.  reported that there were no serious adverse effects. Although the overall incidence of dugs side effects was higher with tadalafil, this difference was not statistically significant (14.6% vs. 29.5%, P = 0.099).
The main limitations of our study were the relatively small sample size, and we did not assess the frequency of sexual intercourse which may be related to stone expulsion. However, to best of our knowledge, this is the first randomized study to evaluate the effect of the combination of silodosin plus vardenafil as a MET. Hence, further studies on a larger number of patients will help to establish the role of combination silodosin plus vardenafil as a medical expulsive therapy for lower ureteric stones.