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at time of writing, Student, College of Pharmacy, University of Toledo, Toledo, OH; now, Staff Pharmacist, The Toledo Hospital, Toledo
Professor of Clinical Pharmacy, College of Pharmacy, University of Toledo; Adjunct Associate Professor of Medicine, Medical University of Ohio at Toledo
Reprints: Dr. Mauro, College of Pharmacy, University of Toledo, 2801 W. Bancroft St., MS 609, Toledo, OH 43606, fax 419/530-1950, LMauro{at}utnet.utoledo.edu
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Abstract |
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 Top Abstract Data SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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1-adrenoreceptor antagonists tamsulosin, terazosin,
and doxazosin in the expulsive treatment of ureteral calculi.
DATA SOURCES: Literature was searched via MEDLINE (1966-February
2006) with subsequent bibliographic review. MeSH headings included ureteral
calculi, nifedipine, doxazosin, and adrenergic -antagonists. Key terms
were ureteral calculi, nifedipine, tamsulosin, terazosin, and doxazosin.
STUDY SELECTION AND DATA EXTRACTION: Trials evaluating nifedipine, tamsulosin, terazosin, and doxazosin for expulsion of ureteral stones were reviewed. All were published in English-language, peer-reviewed journals.
DATA SYNTHESIS: Several trials have evaluated the effects of nifedipine and tamsulosin on ureteral stone passage rates and mean time to stone passage in stones no larger than 15 mm. In 28 day trials, the rates of ureteral stone passage were 35-70% in the control groups compared with 77.1-80% in patients treated with nifedipine and 79.3-100% in patients treated with tamsulosin. Average number of days to stone passage in the control groups was 4.6-20, and the time to stone passage was only 5-9.3 days in patients receiving nifedipine and 2.7-7.9 days in those receiving tamsulosin. The stone passage rates and time to stone passage appeared to be similar in one trial that compared tamsulosin with terazosin and doxazosin. Limited data suggest that these agents may have a role as adjuncts to shock wave lithotripsy. Adverse drug reactions were uncommon.
CONCLUSIONS: Nifedipine, tamsulosin, terazosin, and doxazosin are safe and effective options in enhancing ureteral stone expulsion in selected patients with uncomplicated presentations.
Key Words: doxazosin, nifedipine, tamsulosin, terazosin, ureteral calculi
Published Online, July 18, 2006. www.theannals.com, DOI 10.1345/aph.1G586
The likelihood that calculi will pass through the ureters is dependent on several factors, including size and location within the ureter.1,5,6 Smaller stones, particularly those less than 5 mm in size, are far more likely to pass spontaneously1,4 and may require only observation and management of symptoms. Stones up to 6 mm may require up to 40 days to pass spontaneously,1 and patients should be informed of the likelihood of stone passage when stone size is determined. Symptoms may include excruciating pain due to ureteral colic that often leads to emergency department visits. The duration of observation depends on patient preference, symptoms, and the development of complications necessitating intervention.4 When stones are not expected to pass, do not pass spontaneously, or become problematic, more invasive treatment is recommended. The American Urological Association and the European Association of Urology guidelines for the treatment of ureteral calculi recommend appropriate evidence-based use of shock wave lithotripsy (SWL), percutaneous nephrolithotomy, or ureteroscopy depending on stone size and location within the ureter.4,7 These invasive treatment modalities are also expensive. The costs of SWL and ureteroscopy were recently estimated at $4225.40 and $2644.50, respectively.8
If ureteral stones could be expelled with pharmacotherapy, these procedures
and associated costs could be avoided. Additionally, if the efficacy of these
procedures could be improved pharmacologically, the cost of further and repeat
procedures could be reduced. Calcium-channel blockers, particularly
nifedipine, have been shown to decrease spontaneous contractions of the ureter
by blocking the calcium influx necessary for smooth muscle
contraction,9
which may allow normal peristalsis to move the stone through the ureter.
Similarly, the antagonism of 1-adrenoreceptors by
tamsulosin, which has specificity for 1A- and
1D-adrenoreceptor subtypes, or the nonspecific
1-adrenoreceptor antagonists terazosin and doxazosin
may produce comparable results. The density of
1-adrenoreceptors is higher in the distal ureter than
in other areas of the ureter, and the proportion of
1D-adrenoreceptors is also higher
distally.10
Recent evidence supporting the potential use of nifedipine and the
1-adrenoreceptor antagonists is reviewed here.
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Study Limitations |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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Patient selection criteria in the available trials were fairly uniform. Average ureteral stone size in most studies ranged from approximately 5 to 8 mm. Unless otherwise specified, groups within each trial were similar with regard to age and stone size, and patients with complications such as hydronephrosis, urinary tract infection (UTI), diabetes, or declining renal function were excluded, as they would likely receive more aggressive initial treatment.
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Nifedipine Trials |
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A subsequent trial investigated the expulsive effects of once-daily sustained-release nifedipine for a maximum of 28 days with the corticosteroid deflazacort 30 mg daily for up to 10 days on stones in the distal ureter.13 The treatment group also received gastroprotective misoprostol 200 µg twice daily. Other patients received no drug therapy other than analgesia. Despite excluding patients with a history of hypotension or systolic blood pressure less than 110 mm Hg, 2 patients in the treatment group discontinued therapy because of hypotension and palpitations. The stone passage rate in the treatment group was significantly higher than in the control group, and the time to passage was significantly longer in the control group than in the treatment group. Both the mean daily and total usages of diclofenac were greater in the control group. However, since this trial was neither double-blind nor placebo-controlled and the treatment group received multiple drugs that the control group did not (nifedipine, deflazacort, and misoprostol), the individual role of nifedipine in these results is not clear.
Cooper et al.14 studied the efficacy of a regimen that included a 7 day course of extended-release nifedipine daily, trimethoprim/sulfamethoxazole (TMP/SMX) 160/800 mg daily, and acetaminophen 650 mg 4 times daily with a 5 day course of prednisone 10 mg twice daily for expulsion of ureteral stones. All patients received prochlorperazine suppositories and oxycodone with acetaminophen as needed and were monitored for 42 days. This study excluded only patients with UTI or a history of ureteral stricture and, despite hypotension or therapy with calcium-channel blockers not being exclusion criteria, hypotension was not noted. The expulsion rate was higher in patients in the treatment group than in the control group, and a reduction in workdays lost was also noted with nifedipine (1.76 days with nifedipine vs 4.96 days for control; p = 0.024). However, no significant difference in average time to stone passage was seen. This may be related to the shorter duration of nifedipine therapy than was used in other trials or to the relatively smaller stone size included in this study.
A nonrandomized trial compared sustained-release nifedipine daily and prednisolone 25 mg daily with prednisolone alone for passage of ureteral stones.15 The stone passage rate was greater in the treatment group than in the group receiving only prednisolone, and the time to passage was shorter in patients receiving nifedipine; however, statistical analysis was not performed in this small trial. The relative effect of nifedipine was seemingly not as large as in some of the previous trials, but this is perhaps due to the inclusion of patients with larger stones.
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1-Adrenoreceptor Antagonist Trials
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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ervenàkov et
al.16 were
the first to evaluate the efficacy of tamsulosin in the expulsion of distal
ureteral stones. All patients received tramadol 50 mg and diazepam 5 mg once,
as well as escin 40 mg and diclofenac 50 mg 3 times a day. Stone passage rate
was higher in the treatment group than in the control group, but statistical
analysis was not performed. Although the use of escin rather than a
corticosteroid makes these results difficult to compare with those of other
studies, the findings prompted other investigators to evaluate tamsulosin
efficacy in longer trials. A slightly longer (14 days) trial evaluated the impact of tamsulosin therapy on the efficacy of a standard regimen that included not only escin 80 mg daily, but also omeprazole 20 mg daily, diclofenac 100 mg daily, and levofloxacin 250 mg daily for 7 days.17 Patients were stratified prior to randomization according to age, sex, and stone size. The stone passage rate was significantly higher in the group receiving tamsulosin, and the time to stone passage was significantly shorter. The hospitalization rate was also significantly lower for the group receiving tamsulosin (9 vs 21%; p = 0.01). A trial with slightly larger stones and similar methodology, conducted by many of the same investigators as the previous trial, yielded similar results, including significantly reduced hospitalization rate (10 vs 27.5%; p = 0.01).18
A longer study evaluated the passage of ureteral stones with tamsulosin versus symptomatic treatment for 42 days.19 The investigators did not identify a significant difference in distal stone passage rates between the tamsulosin and control groups. Similar expulsion rates were seen when patients with 6 mm stones were evaluated separately from those with stones larger than 6 mm. Given that the average time to stone passage was not reported, the similar passage rates may be related to the longer treatment duration of 42 days, approaching the time when stone passage would spontaneously occur.
A similar 28 day trial analyzed not only expulsion rates, but also hospitalization and ureteroscopy rates in comparing the efficacy of tamsulosin with that of the antispasmodic agent phloroglucinol.20 Both groups also received deflazacort 30 mg daily for up to 10 days and TMP/SMX (80/400 mg) twice daily for 8 days. Mean stone size was significantly larger in the treatment group receiving tamsulosin than in the group receiving phloroglucinol, but the stone passage rate was significantly higher in patients treated with tamsulosin than in the phloroglucinol group. Tamsulosin therapy also significantly decreased the average time to passage of the stone. When adjusting for various patient factors, only treatment with tamsulosin predicted stone passage (p < 0.001; HR 3.711; 95% CI 1.994 to 6.906). Hospitalization rate was significantly lower with tamsulosin than with phloroglucinol (0% and 33%, respectively; p < 0.0001), and the ureteroscopy rate was similarly reduced (0% and 30%; p < 0.001). Since phloroglucinol has significant antispasmodic effects, there was no true control group in this trial.
Tekin et
al.21
described preliminary data on the efficacy of the
1-adrenoreceptor antagonist terazosin for distal
ureteral stones. The passage rate was significantly higher with terazosin than
with symptomatic treatment. When only stones smaller than 8 mm were
considered, the passage rate in the terazosin group was higher than in the
control group (95 vs 56%; p = 0.005); however, there was no significant
difference in passage rates of stones larger than 8 mm between groups
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Comparative Trials |
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In another 3-armed trial, Dellabella et
al.23
compared the expulsive efficacy of tamsulosin, nifedipine, and
phloroglucinol—all given with deflazacort 30 mg daily. Patients also
received TMP/SMX 160/800 mg daily. Despite the stones being significantly
larger in the tamsulosin group, that group had a significantly higher stone
passage rate than either the group receiving sustained-release nifedipine or
the group receiving phloroglucinol. Median times to passage were significantly
shorter with tamsulosin than with nifedipine and phloroglucinol (3 vs 5 vs 5
days, respectively). Rates of hospitalization were significantly less for
tamsulosin than for nifedipine and phloroglucinol (1.4%, 20%, and 34.3%,
respectively; p 
0.0001). A similar reduction in ureteroscopy rate with
tamsulosin (1.4%) relative to nifedipine (20%) and phloroglucinol (31.4%) was
noted (p 0.0001). Treatment with tamsulosin also resulted in a
significant reduction in median workdays lost (2 days) compared with
nifedipine (3 days; p = 0.001) and phloroglucinol (5 days; p < 0.0001), and
the median workdays lost with nifedipine was significantly less than with
phloroglucinol (p < 0.003).
The comparative efficacy of the 1-adrenoreceptor
antagonists tamsulosin, terazosin, and doxazosin was evaluated in a controlled
trial.24 The
control group had a significantly lower stone passage rate (53.57%) than did
the treatment groups. Average time to stone passage was also significantly
longer in the control group compared with the treatment groups. None of the
patients in this trial received corticosteroids or antispasmodic agents, which
permits more accurate assessment of the absolute efficacy of these specific
agents. The authors concluded that all of these drugs appeared to be effective
ureteral expulsive agents and that corticosteroid therapy may not be
necessary.
This theory that corticosteroids were not necessary for the expulsion of ureteral stones was further tested in a comparison of tamsulosin plus deflazacort with tamsulosin monotherapy.25 Expulsion rates of the tamsulosin and tamsulosin/deflazacort groups at study end were similarly high. The median time to stone expulsion was shorter in the group receiving both tamsulosin and deflazacort (5 vs 3 days). The rates of emergency department visits, hospitalizations, and lost workdays were similar between the 2 groups. The authors concluded that the addition of deflazacort resulted in expulsion rates similar to those of tamsulosin alone, but that time to expulsion may be lessened.
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Pharmacotherapy Plus Lithotripsy |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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A 4-armed trial compared tamsulosin with observation in stones smaller than 5 mm and tamsulosin following SWL with SWL alone for stones between 6 and 15 mm.27 When the stones were less than 5 mm, in the absence of SWL, there was no statistically significant difference in stone passage rates between the group receiving tamsulosin and the control group (p = 0.128). In these small-stone groups, statistical analysis is limited by low patient numbers. In patients who had larger stones and received SWL, the stone passage rates were significantly higher in the group that subsequently received tamsulosin than in the control group. Overall, when stone size is not considered, patients who received tamsulosin had a higher stone passage rate (64.1%) than those who did not (28.2%; p = 0.0015; OR = 4.544; 95% CI 1.746 to 11.830). Tamsulosin treatment was not evaluated in patients with stones measuring 6-15 mm who did not receive SWL.
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Adverse Reactions |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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1-adrenoreceptor
antagonists. In patients receiving nifedipine, the most serious adverse events
reported were hypotension and palpitations. While hypotension was not
uniformly noted in some trials, in studies that initially excluded hypotensive
patients, a small fraction of those receiving nifedipine was unable to finish
due to hypotension and/or palpitations (1 of
43,12 2 of
48,13 1 of
3022). A low
incidence of headache was noted in 3 trials (1 of
43,12 3 of
48,13 1 of
4026),
although one of these studies excluded patients with a history of
headaches.12
Asthenia developed in 8 of
4813 and 3
of 4026
patients receiving nifedipine. With tamsulosin, transient hypotension was reported in 1 of 3217 and 2 of 50 patients,18 and dizziness in 1 of 50,18 5 of 30,19 and 1 of 39 patients.27 Asthenia was reported in 1 of 32,17 1 of 50 (with dizziness),18 and 1 of 2822 patients receiving tamsulosin.
Overall, adverse effects with each of the expulsive therapies were both uncommon and consistent with the known adverse effect profiles of the drugs. In some cases, this may have been due to the exclusion of patients who were likely to experience the particular effects of the medications being administered (eg, hypotensive patients or those already on calcium-channel blockers). In most of the studies, the incidence of adverse effects was determined solely from patient-reported data. In some trials, adverse events, particularly those defined as minor, were not qualitatively described. The inclusion of other drugs, such as corticosteroids, escin, and phloroglucinol, may have contributed to adverse events.
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Discussion |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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1-adrenoreceptor antagonists, based on one
trial,24
appear to have expulsion rates similar to those of tamsulosin. In one
comparative
trial,23
tamsulosin improved stone passage rates and time to stone passage more than
nifedipine did. The same trial demonstrated lower rates of hospitalization and
ureteroscopy and fewer workdays lost with tamsulosin than with nifedipine.
A number of trials have demonstrated benefits of expulsive therapies on
quality-of-life endpoints such as ureteroscopy and hospitalization rates, as
well as work days lost. Hospitalization rates were significantly reduced from
9-34% for controls to 0-9% for tamsulosin and 20% for nifedipine. Ureteroscopy
rates were similarly reduced from 30-31% in controls to 0-1.4% with tamsulosin
therapy and 20% with nifedipine. Workdays lost have also been decreased from 5
to 2 days for tamsulosin and by 1.76-3 days for nifedipine. Although no formal
cost-benefit analysis has evaluated expulsive therapy of ureteral stones,
significant cost savings could arise from this therapy. The costs of
ureteroscopy and SWL range from approximately $2600 to $4200. The costs of
therapy for a typical 28 day course of one of the
1-adrenoreceptor antagonists or nifedipine range from
$27.95 to $57.38, based on the average wholesale
price.28
Limited data suggest that the addition of expulsive therapy to SWL may improve
stone clearance. An adjunctive role for these agents may allow for avoidance
of repeat SWL procedures, resulting in additional potential cost savings.
Patient selection criteria for expulsive therapy are derived from the entry
criteria of the available studies. To avoid potential increased risk of kidney
damage, expulsive therapy should be avoided in patients with hydronephrosis,
UTI, a lone kidney, or diabetes. Hypotension and antihypertensive therapy
(especially with calcium-channel blockers) were common exclusion criteria from
these studies. The relative lack of hypotension and its related adverse
effects (headache, dizziness) likely resulted from the exclusion of these
patients. In the described studies, most stones were no larger than 15 mm and
were located in the distal ureter, so the potential efficacy of nifedipine and
the 1-adrenoreceptor antagonists tamsulosin,
terazosin, and doxazosin may be best supported with similarly sized and
positioned stones.
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Summary |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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References |
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TopAbstractData SourcesStudy LimitationsNifedipine Trials{alpha}1-Adrenoreceptor...Comparative TrialsPharmacotherapy Plus LithotripsyAdverse ReactionsDiscussionSummaryReferences |
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ervenàkov J, Fillo J, Mardiak J,
Kope
n
M, 
mirala J, Lepie
P. Speedy elimination
of ureterolithiasis in lower part of ureters with the alpha
1-blocker—tamsulosin. Int Urol Nephrol 2002;34:25-9.[CrossRef][Medline]This article has been cited by other articles:
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  R. L Losek and L. S Mauro Efficacy of Tamsulosin with Extracorporeal Shock Wave Lithotripsy for Passage of Renal and Ureteral Calculi Ann. Pharmacother., May 1, 2008; 42(5): 692 - 697. [Abstract] [Full Text] [PDF]
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