INTRODUCTION: There are a variety of treatment options available for management of lower ureteral stones. Recent studies have shown the efficacy of some types of drug therapy. The present investigation was a prospective study with randomized patient groups. The purpose was to compare the efficacy of tamsulosin and nifedipine, two commonly prescribed drugs used in medical expulsive therapy for distal ureteric stones.
METHODS: A total of 171 patients with distal ureteral stones < 1 cm in diameter were randomly divided into 3 groups and given medications for a period of 30 days. Patients in all 3 groups received: (1) prophylactic ciprofloxacin (500 mg) 2 times/day for 1 week; (2) Rowatinex capsules (100 mg) 3 times/day until the stone was expelled; (3) EPIMAG magnesium citrate effervescent sachets (2.125 g) dissolved in water 3 times/day until the stone was expelled; (4) diclofenac sodium tablets (50 mg) 2 times/day for 1 week. In addition to the fixed medications described above, patients in group 1 (n = 58) were treated with tamsulosin (0.4 mg) 1 time/day for a maximum of 30 days; patients in group 2 (n = 57) took slow-release nifedipine (30 mg) 1 time/day for a maximum of 30 days. Patients in group 3 (n = 56) were not given tamsulosin or nifedipine. The variables measured were stone expulsion rate, time of expulsion, and number and severity of pain attacks. ANOVA and chi-square tests were used for statistical analysis.
RESULTS: There were no statistically significant differences between the 3 groups on characteristics of sex, age, stone size, or stone laterality. Results showed that 89.6% of the patients taking tamsulosin (group 1) expelled their stones within 30 days, compared with 66.6% of the patients taking nifedipine (group 2) and 57.1% of patients taking only analgesics (group 3). The difference between group 1 and the other groups was statistically significant. Patients taking tamsulosin expelled the stones in a significantly shorter amount of time than patients in the other 2 groups. They also had significantly fewer pain attacks and needed fewer analgesics. Patients taking nifedipine did not have any significant benefits over patients in the other 2 groups.
CONCLUSION: Medical expulsion therapy for lower ureteric stones is a successful procedure. Adding an α-1 adrenergic blocker such as tamsulosin to the treatment regimen is recommended before undertaking any more invasive intervention.
KEYWORDS: Ureter; Stones; Tamsulosin; Nifedipine
CORRESPONDENCE: Dr. Tarek Salem, Rehab City, Modern Cairo, Group 94, Building 4, Flat 11, Cairo, Egypt ().
CITATION: UroToday Int J. 2009 Oct;2(5). doi:10.3834/uij.1944-5784.2009.10.05
INTRODUCTION
Some healthcare professionals recently have been using pharmacology to increase the rate of urinary stone passage. Research has focused on the effectiveness of the two most commonly used medical therapies for small distal ureteral calculi in the juxtavesical or intramural tract: calcium channel blockers and the α adrenergic blocker tamsulosin.
Renal colic, one of the most painful conditions that may occur, is often caused by a stone in the distal portion of the ureter. A trial of conservative therapy is warranted for the majority of ureteral stones in the absence of infection and severe obstruction. Studies have shown a spontaneous passage rate of 71% to 98% for small (< 5 mm) distal ureteral stones [1,2].
The efficacy of minimally invasive therapies such as extracorporeal shockwave lithotripsy (ESWL) and ureteroscopy (URS) has been proven by several studies [1,3]. Nevertheless, these techniques are not risk-free and they are expensive [4].
The use of hormones, nonsteroidal or anti-inflammatory drugs, calcium channel blockers, corticosteroids, and α adrenergic antagonists have all been proposed as a way to enhance stone passage. Hormones including prostaglandins and glucagons are of historical interest only at the present time [5,6].
Smooth muscle in the ureter is the basic anatomic unit. It is affected by the concentration of calcium. An increase in calcium concentration causes contraction; a decrease in calcium concentration causes relaxation. Ureteral stones induce spasms which arrest stone passage [7]. Blocking calcium action on cells has been proposed to decrease ureteral spasm and subsequently decrease the pain and facilitate stone movement.
Studies have demonstrated that both α and ß adrenergic receptors are located in the human ureter, although the α receptors predominate [8]. The α receptors are subclassified into 2 subtypes, α1 and α2. In turn, α1 receptors are further subclassified into α1A (proximal urethra, prostate, bladder outlet), α1B (vessels, smooth muscles), and α1D (detrusor, lower ureter) [9]. The α1D receptors predominate in the lower ureter, particularly the intramural part. The detrusor muscles are ideal targets for pharmacotherapy because they represent the greatest impediment to stone passage. Tamsulosin is uroselective for α1A and α1D, resulting in an overall improvement in the bladder outflow symptoms due to benign prostatic hyperplasia (BPH). Because α1A and α1D receptors predominate, they also cause relaxation of the smooth muscles of the lower ureter, facilitate stone passage, and relieve pain.
A few randomized studies have been done to verify the efficacy of different drug combinations for the spontaneous expulsion of distal ureter stones. These trials have produced interesting results, achieving elimination rates > 80% and excellent pain control [7,10]. It was recently reported that tamsulosin as a selective α1A-α1D antagonist, combined with corticosteroid and appropriate antibiotic, facilitated expulsion of juxtavesical ureteral stones. Additionally, the patients had an almost complete decrease in painful symptoms until there was complete expulsion of the stones [8].
Further drug comparisons are needed to see if the elimination rate can be improved. The current study was performed to assess the expulsive effects of orally administrated tamsulosin and nifedipine for small (< 10 mm) distal ureter calculi.
METHODS
Participants
The participants were 171 patients with acute renal colic, referred from the emergency room or urology clinic in Al-Ansari Specialist Hospital in Yanbu Saudi Arabia. The patients were recruited between January 2006 and December 2007.
All patients underwent physical examination and routine urine analysis. Serum creatinine and serum uric acid were measured. Patients also had kidney, ureter, and bladder plain film (KUB) and ultrasound of the urinary tract (U/S UT). All patients seen in the emergency room received intravenous fluids in the form of 250 cc saline with hyoscine butylbromide (Buscopan ampoules; Boehringer Ingelheim, Berkshire, UK), together with 75 mg intramuscular diclofenac Na ampoules (after a skin sensitivity test).
Criteria for inclusion in the study were: (1) male or female over 18 years old; (2) stones in the lower part of the ureter below the lower border of the sacroiliac joint; (3) stones < 10 mm in longitudinal diameter; (4) no change or mild fullness or mild dilatation of the pelvicalyceal system at the stone side.
Exclusion criteria included: (1) stones in the upper or middle ureter; (2) marked back pressure on the affected side; (3) previous surgical or endoscopic interventions on the affected side; (4) bilateral stones; (5) urinary tract infections; (6) patients with diabetes mellitus, gastric or duodenal ulcer, or hypotension; (7) women who were pregnant or lactating; (8) patients being treated with α-blockers; (9) persons with known hypersensitivity to nifedipine or tamsulosin.
Procedure
Patients meeting all criteria for the study were randomly divided into 3 groups.
Fixed medications for all 3 groups. Patients in all 3 groups received: (1) prophylactic ciprofloxacin (500 mg) 2 times/day for 1 week; (2) Rowatinex (Rowa Pharmaceuticals, Bantry, Co. Cork, Ireland) capsules (100 mg) 3 times/day until the stone was expelled; (3) EPIMAG (Egyptian International Pharmaceutical Industries, Tenth of Ramadan City, Egypt) magnesium citrate effervescent sachets (2.125 g) dissolved in water 3 times/day until the stone was expelled; (4) diclofenac sodium tablets (50 mg) 2 times/day for 1 week.
Group 1 treatment. In addition to the fixed medications, patients in group 1 (n = 58) were treated with tamsulosin (0.4 mg) 1 time/day for a maximum of 30 days.
Group 2 treatment. In addition to the fixed medications, patients in group 2 (n = 57) took slow-release nifedipine (30 mg) 1 time/day for a maximum of 30 days.
Group 3 treatment. Patients in group 3 (n = 56) were treated with only the fixed medications, without tamsulosin or nifedipine.
All patients were allowed to use diclofenac injection (75 mg) as needed, up to a maximum of 2 times/day. They were instructed to drink at least 2 L of fluids daily.
Patients were reevaluated 1 time/week for a period of 1 month, which constituted the end of the study period. Patients received KUB and U/S UT at each evaluation. They were also asked if they had seen stone passage during urination. Patients who failed to expel the stones by the end of the month were advised to have either ESWL or URS, or continue to wait for the stone to expel under medical treatment rendered for an additional month.
Data Analysis
The variables measured were stone size, expulsion rate, time of expulsion, and number of pain attacks. Treatment failure was defined as: (1) the stone was not expelled within 1 month from the start of drug treatment; (2) the patient did not come for regular follow-up; (3) the patient had uncontrollable pain, necessitating additional intervention; (4) there was elevation of serum creatinine > 2 mg/dL, indicating negative reaction to the drugs.
Statistical analysis was done on a personal computer using software SPSS version 10 (Chicago, IL). Descriptive statistics were calculated. Comparison between groups was accomplished using one way analysis of variance (ANOVA) for continuous variables and chi-square test for categorical variables. P < .05 was considered statistically significant.
RESULTS
Table 1 contains the demographic characteristics of sex, age, side of the stone location, and stone size for the patients in the 3 groups. There were no statistically significant differences between groups for any of these variables (P> .05).
None of the patients had an increase in serum creatinine, needed narcotic injection for pain, or developed serious side effects to the treatments. There were no hospitalizations for any reason.
Stone Expulsion
Results of the data analysis showed that 52 out of 58 (89.6%) patients in group 1, 38 out of 57 (66.6 %) patients in group 2, and 32 out of 56 (57.1%) patients in group 3 expelled the stones by the end of the 1 month study period. Patients in group 1 had a significantly higher rate of expulsion when compared with patients in group 2 (P < .05) and group 3 (P < .01). No statistically significant difference in the rate of expulsion was found between group 2 and group 3 (P > .05).
Table 2 shows the time of stone expulsion for patients in the 3 groups. Patients in group 1 had a significantly faster rate of stone expulsion when compared with patients in group 2 (P < .05) and group 3 (P < .05). There were no significant differences in the time of expulsion between group 2 and group 3 (P > .05).
Severe Renal Colic Episodes
Table 3 contains the number of severe renal colic episodes for patients in all groups. Patients in group 1 had significantly fewer pain episodes than patients in group 2 (P < .05) or group 3 (P < .05). There was no significant difference in the number of pain episodes between patients in group 2 and group 3 (P > .05).
DISCUSSION
There are a variety of treatment options available for management of lower ureteral stones, depending on the site and size of the stones and the condition of the upper urinary tract. Some urologists prefer to observe the patient and wait to see if the stone will pass without treatment. Others prefer minimal or noninvasive intervention from the start. ESWL is a noninvasive procedure, but it involves high cost and a significant percent of retreatment. Ureteroscopic stone extraction is considered the gold standard of invasive procedures for lower ureteric stones, and it may be followed by ESWL. However, recently some additional conservative treatment approaches have started to evolve.
Ueno et al [11] evaluated more than 500 patients and reported a spontaneous stone expulsion rate of 57% for 5 mm calculi. Kinder et al [12] reported a 94% spontaneous expulsion rate for stones ≤ 5mm and a 45 % rate for calculi greater than that size.
Other researchers have focused their studies on drugs that can modify ureteral motility to help stone expulsion. These drugs cause smooth muscle relaxation of the lower ureteric segments. The relaxation decreases peristaltic movements, which can decrease the pain and help stone passage.
More medications have been added to the conservative treatment regimen to help in spontaneous stone passage. For example, Bajor [13] gave 86 patients with stones a ß blocker. He found that this drug facilitated stone expulsion and decreased the expulsion time from 11 to 5.2 days without any serious side effects.
Three studies evaluating nifedipine as medical expulsive therapy have been reported to date [7,8,14]. All studies demonstrated a favorable benefit to nifedipine in facilitating stone passage, with only 1 study failing to find statistically significant differences between patients using and not using this drug. Today, α adrenergic antagonists have become preferred to calcium channel blockers for medical expulsive therapy, based on evidence that α-1 receptors have an important role in the physiology of smooth muscle relaxation. This relaxation increases the rate of stone expulsion and decreases pain and analgesic use.
Cervinakov et al [15]conducted a randomized-patient study and found a statistically significant difference in stone expulsion rate between the group treated with tamsulosin and the control group. Several recent clinical trials have shown that α-1 blockers are useful for control of stone colic as well as stone expulsion [8,15,16].
Porpilgia et al [16] sought to determine if the success of treatment with nifedipine and corticosteroid was a result of a single drug or association of the two. They found that the corticosteroid reduced the edema around the stone. The antispasmodic effect of the nifedipine inhibited the stone-induced spasm, maintaining the peristaltic rhythm. Therefore, they found that both treatments in combination were better than either single drug treatment.
De Sio et al [17] recently published a study of 96 patients with distal ureteral stones, randomized into 2 groups. Group 1 (n = 46) received diclofenac (100 mg) daily plus aescin (80 mg) daily; group 2 (n = 50) received the same treatment plus tamsulosin (0.4 mg) daily for a maximum of 2 weeks. The group taking tamsulosin achieved significantly higher rates of stone passage (90% vs 58.7%) over a shorter time period (4.4 vs 7.5 days). They also had lower analgesic use and fewer hospitalizations.
Tamsulosin has a proven effect on the lower urinary tract because of higher density of the α-1 receptors in the lower part of the ureter [18]. The present study was designed to test the effectiveness of tamsulosin on the management of ureteric stones. It was compared with nifedipine, another drug commonly used in the management of lower ureteric stones. The study was limited to patients with lower juxtavesical and intramural ureteric stones with stone size < 10 mm. A maximum observation period of 30 days was chosen because a longer period can increase the complication rate by 20% [19].
The results confirmed the excellent efficacy of tamsulosin for all variables studied. More patients taking tamsulosin (89.6%) were able to expel their stones when compared with the patients in groups 2 and 3 (66.6% and 57.1%, respectively). Patients taking tamsulosin also expelled the stones in significantly fewer days. Tamsulosin decreased the frequency of pain attacks and pain associated with stone passage, as well as analgesic use. Patients taking nifedipine did not have any significant benefits over patients in the other 2 groups.
Tamsulosin decreased the rate of invasive and minimally invasive procedures needed to eliminate small stones. It is an efficient, affordable, effective, and safe method for stone management. The author recommends its use before undertaking any more invasive intervention.
CONCLUSIONS
The results of the current study reveal that medical treatment for stones < 1 cm in the lower ureter could be managed medically with α adrenergic blockers, especially tamsulosin, provided there is no contraindication such as infection or severe obstruction. Patients using it for 1 month did not show side effects from the medicine. Patients benefitted from the pain-relieving effect of the α blocker during treatment. More research is needed to show its application for stones in the middle and upper ureter.
Conflict of Interest: None declared.
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