You are on page 1of 8

EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Medical Treatment for Renal Colic and Stone Expulsion

Panagiotis Kallidonis a, Despoina Liourdi b, Evangelos Liatsikos a,*


a
Department of Urology, University of Patras, Patras, Greece
b
Department of Nephrology, University of Patras, Patras, Greece

Article info Abstract

Keywords: Urinary tract calculi have plagued humans since the dawn of civilization. The
Alfuzosin obstruction of the urinary tract by calculi at the narrowest anatomic areas
Desmopressin (ureteropelvic junction, near the pelvic brim, ureterovesical junction) leads to
Diclofenac impaired drainage, which usually eventually causes the agonizing pain of renal
Expulsion colic. The primary objective of the therapeutic management of urolithiasis is to
ESWL provide relief of pain during an event of acute renal colic. Current evidence suggests
Ketorolac that nonsteroidal anti-inflammatory drugs and opioids are the ‘‘traditional’’
Nifedipine choices, and some specific agents also may be effective. Adverse events of the
Opioids medication administered for the management of renal colic should be considered
Phosphodiesterase inhibitor before using these agents.
Renal colic An additional aim of the urologist is to overcome the obstruction and to preserve
Stone renal function. Medical expulsion therapy for ureteral stones has been suggested as
Tamsulosin a method of conservative management of ureteral stones. The aim of this medica-
Ureteral stone tion is to facilitate the passage of ureteral stones, an area that currently seems to be
Vardenafil a field for continuous investigation. Current literature suggests the use of calcium-
channel blockers and a-blockers for facilitating expulsion of stones, regardless of
size. Nevertheless, patients with stones <10 mm could benefit from a reduced
requirement for analgesics and accelerated spontaneous passage of ureteral stones.
# 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Department of Urology, University of Patras Medical School, Rion, 26 500,
Patras, Greece. Tel. +30 2610 999386; Fax: +30 2610 993981.
E-mail address: liatsikos@yahoo.com (E. Liatsikos).

1. Introduction distention of the renal capsule. Clinical differentiation is


very difficult and sometimes unfeasible due to the fact that
Urinary tract calculi have plagued humans since the dawn of these symptoms usually overlap. Rising pressure in the
civilization. The clinical occurrence of urolithiasis was first renal pelvis, due to the obstructive calculus, stimulates the
described in the Aphorisms of Hippocrates. Incidence of local synthesis and release of prostaglandins, which act
urinary stones is 5–12% in white men and 6% in all women [1]. directly on the ureter to induce spasm of the smooth muscle
The obstruction of the urinary tract by calculi at the [2]. An additional pathophysiologic change is renal vasodi-
narrowest anatomic areas (ureteropelvic junction, near the lation, which induces dieresis with subsequent increase of
pelvic brim, ureterovesical junction) leads to impaired intrarenal pressure. Moreover, the ureteral muscular
drainage, which usually eventually cause pain. Two types of contraction induced by prostaglandins leads to disrupted
pain originate from the kidney: Renal colic is induced by an peristalsis and local lactate production. The accumulation of
increase in wall tension and the stretching of the collecting lactate further irritates types A and C nerve fibers in the
system, and noncolicky renal pain is caused by the ureteral walls. These nerves send afferent signals to the

1569-9056/$ – see front matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2011.07.003
416 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422

dorsal root ganglia at T11-L1 levels of the spinal cord and intestines. Last but not least, approximately 90% of the
eventually are interpreted as pain by the cerebral cortex. patients with renal colic present with gross or microscopic
The primary objective of the therapeutic management of hematuria. In the absence of hematuria, the possibility of
urolithiasis is to provide relief of pain during an event of urinary calculi should also be considered [3]. Infection
acute renal colic. Nevertheless, an additional aim of the proximal to obstruction may complicate renal colic and may
urologist is to overcome the obstruction and to preserve be a contributing factor of pain perception.
renal function. Spontaneous passage occurs with almost all Because of the characteristically poor localization of
ureteral stones !2 mm but with only 1% of stones >6 mm visceral pain, paroxysmal renal colic may mimic a variety of
[2]. In an attempt to treat ureteral stones conservatively, the pathologic abdominal or pelvic states. It is paramount to note
use of various substances has been proposed. These that the most frequent misdiagnosis of ruptured abdominal
substances facilitate the passage of ureteral stones and aortic aneurysms is renal colic. Marston et al demonstrated in
increase the likelihood of spontaneous stone expulsion. a retrospective, multi-institution study that 30% of referred
Medical expulsion therapy (MET) has a long history. For cases of ruptured abdominal aortic aneurysms were initially
centuries, high fluid intake was thought to facilitate faster diagnosed incorrectly as renal colic incidents [5].
expulsion of ureteral stones associated with symptoms. The The goal of radiologic evaluation in the setting of renal
increased hydrostatic pressure proximal to the stone and colic is not only to confirm the diagnosis and to identify the
the high urine output inducing ureteral peristalsis are presence of the calculi but also to determine whether urgent
probably the mechanisms of action of high fluid intake on a intervention is required. For suspected stone colic, excretory
ureteral stone [3]. Nevertheless, the effect of high fluid urography (intravenous pyelography) has been the tradi-
intake and diuretics in stone expulsion and pain relief has tional gold standard for decades. However, in recent years,
not been clearly proven in a meta-analysis [3]. Comparison unenhanced helical computed tomography (CT) of the
of normal and high diuresis during a session of extracorpo- abdomen and pelvis has been introduced as the best imaging
real shock wave lithotripsy (ESWL) did not prove to be study and provides a contrast-free, increasingly popular
beneficial in a randomized study [4]. Moreover, the extent alternative for depiction. According to the 2010 European
of ureteral obstruction and the outcome of the high fluid Association of Urology guidelines, in randomized prospective
intake treatment can be predicted, whereas the patient’s studies of patients with acute renal colic, the sensitivity and
discomfort and possible complications are the motives for the specificity of unenhanced helical CT was similar or
investigating the possible use of medication to facilitate superior to that obtained with urography. An alternative
stone expulsion. In this paper, we attempt to review current evaluation method of acute flank pain is the combination of
evidence in the medical treatment of renal colic and MET. plain film of the kidneys, ureters, and bladder with
ultrasonography. Extensive experience shows that in a large
2. Dealing with renal colic proportion of patients, these methods are sufficient for the
diagnosis of a ureteral stone [6]. Ultrasonography is the initial
2.1. Symptoms and evaluation of renal colic imaging method when colic occurs during pregnancy.

Renal colic is typically characterized by the sudden onset of 2.2. Medical treatment of renal colic
colicky flank pain. The severity of the pain depends on the
degree of obstruction and the stone size. The position of the The main target of the therapeutic management of acute
calculus is related not only to the location of the pain but also renal colic is to provide adequate analgesia. In addition,
to pain radiation, thus various anatomic regions may be aggressive hydration is not recommended for the manage-
involved. When the stone is located in the ureteropelvic ment of renal colic because the main target of the therapy is
junction, the patient appears with severe pain of the to eliminate spasms of the ureteral walls. Nevertheless, the
costovertebral angle that radiates along the course of administration of fluids should be considered only in cases
the ureter and the gonad (due to shared innervation). of intractable vomiting. Medical analgesic treatment has
Another possible location for the calculi is the midureter, in gained increasing attention in an attempt to relieve
which case the pain symptoms are almost the same as noted, patients’ pain—not only to achieve reduction in pain score
except that the patient also reports important tenderness of but also to reduce the need for repeat dosing. Two principal
the lower abdominal quadrant. Finally, stones at the distal classes of drugs are used to relieve excruciating pain:
ureter often cause pain that radiates to the groin or testicle in nonsteroidal anti-inflammatory drugs (NSAIDS) and
males and to the labia majora in females; symptoms of opioids. In addition, other pharmacologic agents such as
bladder irritability can usually occur as the stone approaches cyclooxygenase (COX) 2 inhibitors, desmopressin, or a drug
the ureterovesical junction. Furthermore, signs of peritoneal combination can be administered to provide pain relief.
irritation are absent. The patient with acute renal colic is Drugs that are commonly used to treat renal colic are
often writhing in distress, trying to find a comfortable summarized in Table 1. Pain of different severity could be
position in an attempt to release the agonizing pain. In managed according to Heid and Jage, as presented in Table 2
contrast, a patient with peritoneal signs lies motionless to [7]. It is important to note that when medical therapy is
minimize discomfort. In addition, acute renal colic is inadequate to provide pain relief, urinary decompression
frequently associated with nausea and vomiting due to the should be obtained by invasive means, usually percutane-
shared splanchnic innervation of the renal capsule and the ous nephrostomy and double-J stenting.
EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422 417

(if single dose is ineffective


3. Stone expulsion therapy

rhinitis, nausea, dizziness,

anaphylaxis, thrombosis
after 30 min, consider
Desmopressin

hyponatremia, water
Antidiuretics

intoxication, seizure,
NSAIDs or narcotics)

Common: headache,
3.1. Targets of medical expulsion therapy in the ureter

Rare but serious:


40 mg per spray
Understanding the physiology and pathophysiology of the
ureter is important for elucidating the effects of various

epistaxis
medical substances on the ureter. The mechanism of
ureteral contraction is based on the increase of cytoplasmic
sedation, dizziness, constipation, free calcium and the function of calcium channels. Calcium-
Acetaminophen plus codeine

nausea, vomiting, hypotension, channel blockers inhibit the spontaneous rhythmic activity

Rare but serious: respiratory


with 30 mg of codeine, two

rash, biliary spasm, urinary


Common: lightheadedness,
300 mg of acetaminophen

tablets orally every 4–6 h

of the ureter and calyces, whereas prostaglandins and


Combination

depression, hemolytic
calcium influx to the cells induce contractions [8]. The
effects of calcium-channel blockers such as verapamil and
retention, miosis

nifedipine have led to the use of these substances for MET.


Adrenergic receptors are also present in the ureter and
have been pharmacologically identified. These receptors are
a1A, a1B, and a1D. The distal ureter has the higher
distribution of a1 adrenergic receptors [9]. The presence
others similar to those
pressure, bradycardia;
increased intracranial
Morphine sulfate

of a1D is highest among the aforementioned subtypes,


0.1 mg/kg IM or IV

toxic megacolon,

especially in the distal ureter [10]. Heterodimers of different


paralytic ileus,

of meperidine
Biliary spasm,

adrenergic receptors are possible. Heterodimers of a1A with


every 4 h

a1D have not been detected, and the possibility of a1B


having a regulatory role could not be precluded [11].
The presence of the enzymes phosphodiesterase (PDE)
Opioids

dry mouth, urinary retention,

types 1, 2, and 4 in the human ureter has been detected. The


Rare but serious: respiratory
nausea, vomiting, dysphoria,

disorientation, constipation,
lightheadedness, sedation,

inhibition of these enzymes led to relaxation of the ureter


1 mg/kg of body weight

cardiovascular incident
hypotension, agitation,

[12]. At least 11 types of PDE enzymes have been detected


Meperidine

Common: dizziness,

depression, seizure,

COX-2 = cyclooxygenase 2; IM = intramuscularly; IV = intravenously; NSAID = nonsteroidal anti-inflammatory drug.

throughout the body and are responsible for a variety of


IM every 3–4 h

functions. Cyclic adenosine monophosphate (cAMP) and


cyclic guanosine monophosphate (cGMP) are intracellular
flushing

messenger molecules that regulate cellular response to


extracellular stimulation. Intracellular high levels of cAMP
and cGMP lead to a complex cascade of events that result in
hypertension, nausea,
epigastric discomfort,

bleeding, esophagitis,
COX-2 inhibitor

Common: diarrhea,

smooth muscle relaxation. PDE isoenzymes are responsible


dyspepsia, fatigue,
peripheral edema,

Rare but serious:

hypersensitivity,
Rofecoxib

gastrointestinal

for the degradation of intracellular cyclic nucleotides. PDE


bronchospasm,
hypertension

inhibitors increase the intracellular concentration of cyclic


dizziness
50 mg/d

nucleotides and cause smooth muscle relaxation. PDE


isoenzymes 4, 7, and 8 are specific for cAMP, whereas
PDE isoenzymes 5, 6, and 9 are specific for cGMP. The
50 mg orally two or
three times per day

Thrombocytopenia;

remaining isoenzymes of the PDE family have action on


those of ketorolac
others similar to
Diclofenac

both cyclic nucleotides. Experimentation with PDE5 inhibi-


tors has proven that the pig ureter as well as the human
ureter could be relaxed by the cGMP-mediated pathway.
The noted receptors and enzymes have been considered
Table 1 – Commonly used drugs in renal colic

as targets of stone MET. Intense investigation with


dizziness, elevated aminotransferase
oral continuation dose: 10 mg orally

abdominal pain, diarrhea, headache,

levels, drowsiness, tinnitus, pain at

pharmaceutical substances aimed at these targets is


every 4–6 h (maximum: 40 mg/d)
NSAID

30–60 mg IV or IM loading dose,


then 15 mg IV or IM every 6 h;

ongoing, and several clinical and experimental studies are


Common: dyspepsia, nausea,

currently available. These studies include substances such


as a-blockers, anticholinergics, PDE5 inhibitors, calcium-
Ketorolac

channel blockers, and corticosteroids [3]. The effectiveness


not to exceed 5 d

of the majority of the substances remains to be proven, and


injection site

clear results require further investigation. A review of the


current status of MET investigation follows.

3.2. Medical expulsion therapy


Medication

events
Adverse

3.2.1. Cyclooxygenase inhibitors


Dosage

Understanding of the aforementioned mechanism of


prostaglandin action during renal colic and obstruction
418 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422

Table 2 – Severity of renal colic pain and appropriate treatment

Level of pain Moderate Severe Unbearable

Drug dose Diclofenac 100 mg oral/rectal Diclofenac 50–100 mg IV (30 min) Diclofenac 50–100 mg IV (30 min)
or or or
ibuprofen 600–800 mg oral/rectal dipyrone 1–2 g IV (30 min) dipyrone 1–2 g IV (30 min)
or or
5 g dipyrone IV and 500 mg tramadol per 24 h 2–3 mg per dose morphine titrated to effect
or or
Desmopressin 40 mg intranasal pethidine 25 mg per dose IV
or
5 g dipyrone IV and 500 mg tramadol per 24 h
or
Desmopressin 40 mg intranasal

IV = intravenously.

related to the presence of ureteral stones suggested the 3.2.4. Corticosteroids


possible role of NSAIDs in MET because these drugs would The anti-inflammatory action of corticosteroids has been
reduce inflammation and edema at the site of the stone. suggested to facilitate stone expulsion [3]. Methylpredni-
Moreover, the selective COX-2 inhibitor NS-398 has dual sone has been evaluated in a randomized trial and has been
action and decreases tonic or phasic contraction by proven to facilitate distal ureteral stone expulsion [24].
inhibiting the action of voltage-dependent calcium chan- Nevertheless, that study has been published only as an
nels. A nonselective inhibitor of COX (diclofenac) and a abstract. Further reports should be expected to elucidate
selective inhibitor of COX-2 (NS-398) have been observed to the role of corticosteroids in MET.
reduce ureteral contractions in the pig ureter [13].
Nevertheless, diclofenac and celecoxib have been evaluated 3.2.5. a-Blocker therapy
in double-blind trials, and they do not have an effect on the The use of a-blockers for MET has been evaluated
stone expulsion rate in comparison with control groups extensively. A number of studies have assessed the effect
[14,15]. of tamsulosin, alfuzosin, terazosin, and doxazosin in
patients with ureteral stones who have not undergone
3.2.2. Rowatinex ESWL. A recent meta-analysis by Seitz et al showed that
Rowatinex is a special terpenes combination and is a-blockers are associated with benefit for stone expulsion
considered to have diuretic anti-inflammatory and analge- and insignificant reduction of renal colic events [3]. A class
sic properties. In a randomized clinical trial, Rowatinex effect was proposed after similar expulsion rates were
improved stone-free rates and reduced symptomatology observed with tamsulosin, terazosin, and doxazosin [25].
during stone passage [16]. Similar results were reported by Only one trial in the literature uses alfuzosin for MET and
another randomized placebo control study [17]. Neverthe- does not present a significant positive outcome in the
less, a randomized trial comparing tamsulosin 0.4 mg to treatment group [26]. Specifically, tamsulosin was proven to
Rowatinex and diclofenac revealed that tamsulosin provid- have an overall benefit for stone expulsion when compared
ed a significantly higher stone-expulsion rate as well as with a control group. These results were observed with a dose
shorter expulsion time [18]. The role of Rowatinex should scheme of 0.4 mg and 0.2 mg in studies with nonsignificant
be investigated further to draw definitive conclusions. heterogeneity including several hundreds of patients. Similar
results were observed with doxazosin and terazosin when
3.2.3. Antimuscarinics their effects were compared with a control group [25]. A
Experimental data suggest that antimuscarinics may have double-blind placebo controlled trial with the use of
relaxing action on the smooth muscle of the urinary tract alfuzosin demonstrated different results because the spon-
and may reduce renal colic [19]. N-butylscopalamine has taneous passage of stones was not increased by the
been evaluated in a randomized clinical trial and did not substance. Nevertheless, patient comfort and shorter time
reduce the amount of opioid analgesia used in renal colic to stone passage were noted in the alfuzosin group [26].
management in comparison with the control group [20]. The use of a-blockers in patients who have undergone
The same medication was inefficient in reducing renal ESWL has been evaluated extensively in >1000 patients. An
pelvic pressure and provided less favorable outcome in overall benefit for stone expulsion was noted in the meta-
comparison with dipyrone [21]. Another study showed analysis by Seitz et al [3]. In fact, all doxazosin, terazosin,
that the combination of a spasmolytic agent with dipyrone and tamsulosin 0.4-mg trials reported an overall benefit for
does not contribute to the analgesic effect [22]. Moreover, stone expulsion after ESWL, and a class effect should be
the addition of tolterodine to tamsulosin did not provide considered [25]. Reductions in renal colic events and
any benefit in terms of stone expulsion rate [23]. No analgesic requirement were observed in the majority of
evidence shows that antimuscarinics facilitate stone studies [3]. Only one study evaluating the use of tamsulosin
expulsion. 0.2 mg did not report a favorable outcome [27].
EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422 419

3.2.6. a1D Blockers are reported to be significantly reduced with the adminis-
The a1D receptor antagonist naftopidil has been evaluated tration of nifedipine, tamsulosin, doxazosin, and terazosin
recently in 60 patients, and a significant increase of the [3,25].
expulsion rate in comparison to control was observed.
Expulsion time was not improved and adverse events were 4. Discussion
minimal [28]. Similar results for naftopidil were reported in
a comparative study of naftopidil, urapidil, and tamsulosin 4.1. Renal colic management
0.2 mg and control. All groups received additional therapy
with flopropione (antispasmotic) and an herbal extract Providing relief from the debilitating pain caused by
facilitating expulsion [29]. obstructing calculi is a therapeutic challenge. The main
drug categories that are commonly used as analgesic agents
3.2.7. Calcium-channel blocker therapy are NSAIDS (ketorolac, diclofenac), which act directly by
Nifedipine has been used for the spontaneous expulsion of inhibiting prostaglandin-induced effects, and opioids
ureteral stones. Several studies without significant biases (pethidine, meperidine, morphine, and tramadol). Singh
showed higher expulsion rates in comparison with control et al reported that the medical therapy of acute renal colic
groups, and events of renal colic were not reduced [3]. The should be started with NSAIDs. They also claimed that
expulsion of the stones required an average time of up to 12 d. supplementary agents should be added only if excruciating
It should be noted that the majority of the studies include pain is persistent [34]. In a detailed meta-analysis of 20
distal ureteral and vesicoureteral stones [3]. Nifedipine as clinical trials that included 1613 participants, Holdgate and
MET has been used and evaluated in two studies in Pollock demonstrated that administration of NSAIDs to
conjunction with ESWL [25,30]. Stone expulsion benefit patients with acute renal colic provides slightly more
was observed in both studies. efficient pain relief than opioids. Furthermore, they
concluded that opioids, especially pethidine, are highly
3.3. Adverse events of medical expulsion therapy associated with nausea and vomiting incidents. Moreover,
these drugs proved to be inadequate in the treatment of
MET has not been reported to have high rates of adverse renal colic because patients treated with them are more
events, and the majority of patients do not discontinue their likely to need rescue medication [20]. Nevertheless, Safdar
therapy [3]. Variable adverse events and dropout rates have et al compared the efficacy of intravenous morphine,
been reported in trials with tamsulosin and nifedipine. ketorolac, and their combination in a prospective double-
Palpations and hypotension are some of the common blind randomized controlled study. They reported that the
adverse events among the studies (especially with nifedi- combination of 15 mg of ketorolac plus 5 mg of morphine is
pine), and their incidence was minimized if careful patient superior to each drug alone at the same doses. Moreover,
selection was performed. The administration of nifedipine they claimed that patients treated with the combination of
resulted in incidence of 3.3–4.2% for these adverse events in these agents were less likely to need rescue analgesia [35]. It
a patient population excluding hypotensive patients should be noted that the administration of NSAIDs to
[31,32]. Nevertheless, discontinuation of medication was patients with preexisting renal impairment may lead to
not observed in some studies, and adverse events were not further renal deterioration because NSAIDs decrease renal
higher in the treatment group compared with the control blood flow and diuresis [36]. However, in typical doses,
group [3]. It should be noted that some of these studies ketorolac has a low risk of acute renal injury [37]. In
include additional medication with MET (ie, corticoste- addition, minor and major gastric bleeding is a possible
roids), and the adverse event rates may be increased due to principal adverse event of the use of NSAIDs and should be
the additional medication [25]. considered. Patients with high risk of hemorrhagic gastro-
intestinal incidents should be considered for selective COX-
3.4. Additional benefits of medical expulsion therapy 2 inhibitors. Moreover, Snir et al suggested that treatment
with papaverine hydrochloride would be beneficial for
The need for hospitalization has been reduced significantly patients with contraindications for NSAIDs [38].
by the administration of tamsulosin in comparison with the Finally, opioids should be avoided, if possible, because
control group, as several trials have demonstrated [3]. they may result in addiction. Opioid-seeking patients might
Nevertheless, an investigating group showed no benefit in pretend to suffer from acute renal colic in an attempt to
terms of hospitalization with tamsulosin [23]. Nifedipine receive these drugs. Nonetheless, opioids are the medical
resulted in significantly reduced hospitalization rates in therapy of choice during pregnancy, when all other drugs
comparison with the control group (which received are contraindicated because of teratogenic potential.
phloroglucol) [33]. Both tamsulosin and nifedipine have Desmopressin is another option in the treatment of
been associated with reduced numbers of emergency room paroxysmal renal colic. This agent, as a synthetic analog of
visits and numbers of working days lost by patients [3]. vasopressin, has antidiuretic action with subsequent
These results show that MET may have a potential benefit suppression of renal pelvic muscular contractility. Roshani
for the health system and for insurance regarding costs et al assessed the clinical efficacy of intranasal desmo-
related to the use of medical services and loss of working pressin spray plus diclofenac sodium and suggested that
days. The use of analgesic medication and renal colic events intranasal administration of desmopressin is a useful
420 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422

supplemental therapy in combination with NSAIDs [39]. 4.3. Tamsulosin versus nifepidine for medical expulsion therapy
Although the use of spasmolytic anticholinergic agents has
been controversial, Mortelmans et al reported that a The efficacy of tamsulosin versus nifedipine for MET of
continuous intravenous drip of tramadol would be a safe distal ureteral stones has been evaluated in three studies,
and effective alternative option for analgesia [40]. Further- with controversial results [33,48,49]. Keshvary et al did not
more, Hazhir et al showed that the use of the combination of observe any statistical differences in terms of expulsion
desmopressin and tramadol or of each drug alone in rates between the two substances [48]. When stones
patients with renal colic can reduce the pethidine require- <10 mm were treated with tamsulosin or nifedipine in
ment [41]. In a randomized double-blind controlled trial, combination with deflazacort, the expulsion rates were
Djaladat et al evaluated the role of aminophylline as an higher in the tamsulosin group without reaching signifi-
analgesic. They demonstrated that this drug is significantly cance [49]. Dellabella et al used the same medication for the
effective in pain relief because it reduced pain in 64% of the treatment of stones >4 mm. A significantly higher expul-
patients, whereas only 17% of the patients of the control sion rate and a shorter expulsion time was observed in the
group reported pain reduction [42]. tamsulosin group, despite significantly larger stones
(7.2 mm vs 6.2 mm). Hospitalization, loss of working days,
4.2. Medical expulsion therapy and stone size need for endoscopic procedures, and analgesic medication
were significantly lower in the tamsulosin group [33].
Stones with a diameter <4 mm are related to high MET has been proven to be effective in the management
spontaneous expulsion rates that may limit the effective- of ureteral stones after ESWL. In fact, these stones could be
ness of MET [3]. Calcium-channel blockers and a-blocker treated with tamsulosin 0.4 mg, doxazosin, or terazosin
therapy have been administered in patients with stones with favorable outcome in terms of stone expulsion rate and
ranging from 2 mm to 15 mm [3,25]. Alfuzosin and renal colic events [25]. Similar results have been reported
tamsulosin have been assessed in randomized clinical trials for the treatment of renal stones with tamsulosin after
and have demonstrated significantly higher expulsion rates ESWL [3]. Stone-free rates were higher in the tamsulosin
in comparison with controls [26,43]. Nevertheless, alfuzo- group, and larger fragments were expelled. The evaluation
sin has been related to lower effectiveness due to the small of the efficacy of MET for upper ureteral stones revealed that
mean stone size of up to 3.8 mm. The small stone size leads tamsulosin or nifedipine combined with corticosteroid
to high rate of spontaneous passage of stones and probably provided higher expulsion rates [32,50]. This observation
underestimates the effectiveness of alfuzosin [26,44]. could be attributed to the fact that the proximal ureteral
Hermanns et al administered tamsulosin as MET and stones also have to pass through the distal ureter, and
observed that the treatment scheme was not efficient in decreased expulsion time as well as fewer renal colic events
stones with >5 mm, whereas the majority of the stones in would have been favorable [3]. In recent meta-analysis,
both tamsulosin and control groups were <5 mm. The lack Seitz et al proposed the neoadjuvant use of a-blockers or
of an adequate number of stones >5 mm should be calcium-channel blockers in patients undergoing ESWL or
considered in the interpretation of these results, as the ureteroscopy, especially in cases of impacted stones, for
statistical analysis of this subgroup may be underpowered. which the results of ESWL or ureterscopy may be less
The investigating group concluded that the decreasing favorable. In fact, the authors proposed that the early use of
stone size may minimize any potential benefit of MET due drugs that could counteract ureteral spasm in combination
to the high spontaneous expulsion rates of stones <5 mm. with corticosteroids may be beneficial [3].
However, a significant analgesic effect in MET was
observed, and the expulsion rates were improved without 4.4. Corticosteroids for medical expulsion therapy
reaching statistical significance [43]. Similar results have
been reported by Liatsikos et al, who showed relatively The combined administration of tamsulosin or nifedipine
lower expulsion rates with the administration of doxazosin with corticosteroid has been evaluated by some investiga-
for stones <5 mm in comparison to stones 5–10 mm [45]. In tors [3,32,33]. The administration of the combination of
contrast, a study by Cooper et al including cases with mean tamsulosin and corticosteroid was proven to be advanta-
stone size of 3.6 mm did not report a higher expulsion rate geous in terms of expulsion rate when compared with a
in the tamsulosin group [46]. The administration of MET in corticosteroid group and a control group receiving analge-
conjunction with ESWL demonstrated stone-free rates that sics [51]. Similar results were obtained in a study comparing
were significantly improved with increasing size [3,25,44]. phloroglucinol or tamsulosin or nifedipine in combination
Some investigators have observed higher expulsion rates of with a corticosteroid where no correlation between stone
stones >5 mm [47], whereas others have observed higher size and stone expulsion time was observed [33]. These
expulsion rates of stones "11 mm [44,47]. In a study by findings could be attributed to the anti-inflammatory action
Porpiglia et al, the administration of nifedipine resulted in of the corticosteroid for stone impaction [3]. In addition, the
the expulsion of stones significantly larger in the treatment combination of tamsulosin with corticosteroid revealed a
group compared with controls. Thus nifepidine facilitated similar stone expulsion rate but a significantly shorter
the expulsion of larger stones [30]. Considering this, a expulsion time, suggesting a beneficial effect of the
recent review Seitz assumed that the stone expulsion rate combined therapeutic approach; the single use of cortico-
will be greatest in stones between 4 mm and 10 mm [25]. steroids should not be considered [51].
EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422 421

4.5. Cost effectiveness of medical expulsion therapy [9] Sigala S, Dellabella M, Milanese G, et al. Evidence for the presence of
a1 adrenoceptor subtypes in the human ureter. Neurourol Urody-
Only one study evaluated the cost-effectiveness of MET in nam 2005;24:142–8.
[10] Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination
comparison with conservative treatment of distal ureteral
of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol
stones [52]. The study included data from five countries.
2007;14:749–53.
Calculation of cost was based on statistical data of a-blocker
[11] Uberti MA, Hall RA, Minneman KP. Subtype-specific dimerization of
therapy provided by previous investigations, and failures alpha 1-adrenoceptors: effects on receptor expression and phar-
were considered for ureterscopy, which has been consid- macological properties. Mol Pharmacol 2003;64:1379–90.
ered more cost-effective than ESWL. Nevertheless, the study [12] Stief CG, Taher A, Truss M, et al. Phosphodiesterase isoenzymes in
is associated with significant limitations and biases. human ureteral smooth muscle: identification, characterization,
and functional effects of various phosphodiesterase in vitro. Urol
Int 1995;55:183–9.
5. Conclusions
[13] Mastrangelo D, Wisard M, Rohner S, Leisinger H, Iselin CE. Diclo-
fenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease
The treatment of acute renal colic depends on the personal
agonist induced contractions of the pig isolated ureter. Urol Res
experience and the institutional culture of the treating 2000;28:376–82.
physician. Current evidence suggests that NSAIDs and [14] Laerum E, Ommundsen OE, Granseth JE, Christiansen A, Fagertun HE.
opioids are the traditional choices, and some specific agents Oral diclofenac in the prophylactic treatment of recurrent renal
may be effective. Medication administered for the manage- colic: a double-blind comparison with placebo. Eur Urol 1995;28:
ment of renal colic is associated with several adverse events 108–11.
that should be taken into consideration before using these [15] Phillips E, Hinck B, Pedro R. Celecoxib in the management of acute
agents. MET seems to be a field of continuous investigation. renal colic: a randomized controlled clinical trial. Urology 2009;74:

Calcium-channel blockers and a-blockers should be con- 994–9.


[16] Djaladat H, Mahouri K, Khalifeh Shooshtary F, Ahmadieh A. Effect of
sidered for facilitating expulsion of stones regardless of size.
Rowatinex on calculus clearance after extracorporeal shock wave
Nevertheless, patients with stones <10 mm could benefit
lithotripsy. Urol J 2009;6:9–13.
from a reduced requirement for analgesics and accelerated [17] Romics I, Siller G, Kohnen R, Mavrogenis S, Varga J, Holman E. A
spontaneous passage of ureteral stones. special terpene combination (Rowatinex1) improves stone clear-
ance after extracorporeal shockwave lithotripsy in urolithiasis
Funding support patients: results of a placebo-controlled randomised controlled
trial. Urol Int 2011;86:102–9.
[18] Aldemir M, Ucgul JE, Kayigil O. Evaluation of the efficiency of
None.
tamsulosin and rowanitex in patients with distal ureteral stones:
a prospective, randomized, controlled study. Int Urol Nephrol
Conflicts of interest 2011;43:79–83.
[19] Schneider T, Fetscher C, Krege S, Michel MC. Signal transduction
The authors have nothing to disclose. underlying carbachol-induced contraction of human urinary blad-
der. J Phramacol Exp Ther 2004;309:1148–53.
[20] Holdgate A, Pollock T. Systematic review of the relative efficacy of
References non-steroidal anti-inflammatory drugs and opioids in the treat-
ment of acute renal colic. BMJ 2004;328:1401.
[1] Bihl G, Meyers A. Recurrent renal stone disease-advances in patho- [21] Zwergel U, Felgner J, Rombach H, Zwergel T. Aktuelle conservative
genesis and clinical management. Lancet 2001;358:651–6. Behandlung einer Nierenkolik: Stellenwert der Prostaglandin-
[2] Masarani M, Dinneen M. Ureteric colic: new trends in diagnosis and synthesehemmer. Der Schmerz 1998;12:112–7.
treatment. Postgrad Med J 2007;83:469–72. [22] Edwards JE, Meseguer F, Faura C, Moore RA, McQuay HJ. Single dose
[3] Seitz C, Liatsikos E, Porpiglia F, Tiselius H-G, Zwergel U. Medical dipyrone for acute renal colic pain. Cochrane Database Syst Rev
therapy to facilitate the passage of stones: what is the evidence? 2002, CD00386.
Eur Urol 2009;56:455–71. [23] Erturhan S, Erbagci A, Yagci F, Celik M, Solakhan M, Sarica K.
[4] Tiselius HG, Aronsen T, Bohgard S, et al. Is high diuresis an impor- Comparative evaluation of efficacy of use of tamsulosin and/or
tant prerequisite for successful SWL-disintegration of ureteral tolterodine for medical treatment of distal ureteral stones. Urology
stones? Urol Res 2010;38:143–6. 2007;69:633–6.
[5] Marston WA, Ahlquist R, Johnson G, Meyer AA. Misdiagnosis of [24] Salehi M, Fouladi Mehr M, Shiery H, et al. Does methylprednisolone
ruptured abdominal aortic aneurysms. J Vasc Surg 1992;16:17–22. acetate increase the success rate of medical therapy for passing
[6] Preminger GM, Tiselius H-G, Assimos DG, et al. From the American distal ureteral stones [abstract 92]? Eur Urol Suppl 2005;4(3):25.
Urological Association Education and Research, Inc., and the Euro- [25] Seitz C. Medical expulsive therapy of ureteral calculi and supportive
pean Association of Urology. 2007 Guideline for the management of therapy after extracorporeal shock wave lithotripsy. Eur Urol Suppl
ureteral calculi. Eur Urol 2007;52:1610–31. 2010;9:807–13.
[7] Heid F, Jage J. The treatment of pain in urology. BJU Int 2002;90: [26] Pedro RN, Hinck B, Hendlin K, Feia K, Canales BK, Monga M.
481–8. Alfuzosin stone expulsion therapy for distal ureteral calculi: a
[8] Sahin A, Erdemli I, Bakkaloglu M, Ergen A, Basar I, Remzi D. The double-blind, placebo controlled study. J Urol 2008;179:2244–7,
effect of nifedipine and verapamil on rhythmic contractions of hu- discussion 2247.
man isolated ureter. Arch Int Physiol Biochim Biophys 1993;101: [27] Kobayashi M, Naya Y, Kino M, et al. Low dose tamsulosin for stone
245–7. expulsion after extracorporeal shock wave lithotripsy: efficacy in
422 EUROPEAN UROLOGY SUPPLEMENTS 10 (2011) 415–422

Japanese male patients with ureteral stone. Int J Urol 2008;15: [40] Mortelmans LJ, Desruelles D, Baert JA, Hente KR, Tailly GG. Use of
495–8. tramadol drip in controlling renal colic pain. J Endourol 2006;20:
[28] Sun X, He L, Ge W, Lv J. Efficacy of selective alpha1D-blocker 1010–5.
naftopidil as medical expulsive therapy for distal ureteral stones. [41] Hazhir S, Badr YA, Darabi JN. Comparison of intranasal desmopres-
J Urol 2009;181:1716–20. sin and intramuscular tramadol versus pethidine in patients with
[29] Ohgaki K, Horiuchi K, Hikima N, Kondo Y. Facilitation of expulsion renal colic. Urol J 2010;7:148–51.
of ureteral stones by addition of a1-blockers to conservative ther- [42] Djaladat H, Tajik P, Fard SA, Alehashemi S. The effect of aminoph-
apy. Scand J Urol Nephrol 2010;44:420–4. ylline on renal colic: a randomized double blind controlled trial.
[30] Porpiglia F, Destefanis P, Fiori C, Scarpa RM, Fontana D. Role of South Med J 2007;100:1081–4.
adjunctive medical therapy with nifedipine and deflazacort after [43] Hermanns T, Sauermann P, Rufibach K, Frauenfelder T, Sulser T,
extracorporeal shock wave lithotripsy of ureteral stones. Urology Strebel RT. Is there a role for tamsulosin in the treatment of distal
2002;59:835–8. ureteral stones of 7 mm or less? Results of a randomised, double-
[31] Borghi L, Meschi T, Amato F, et al. Nifedipine and methylpredniso- blind, placebo-controlled trial. Eur Urol 2009;56:407–12.
lone in facilitating ureteral stone passage: a randomized, double- [44] Micali S, GrandeM, Sighinolfi MC, De Stefani S, Bianchi G. Efficacy of
blind, placebo-controlled study. J Urol 1994;152:1095–8. expulsive therapy using nifedipine or tamsulosin, both associated
[32] Porpiglia F, Destefanis P, Fiori C, Fontana D. Effectiveness of nifedi- with ketoprofene, after shock wave lithotripsy of ureteral stones.
pine and deflazacort in the management of distal ureter stones. Urol Res 2007;35:133–7.
Urology 2000;56:579–82. [45] Liatsikos EN, Katsakiori PF, Assimakopoulos K, et al. Doxazosin for the
[33] Dellabella M, Milanese G, Muzzonigro G. Randomized trial of management of distal-ureteral stones. J Endourol 2007;21:538–41.
the efficacy of tamsulosin, nifedipine and phloroglucinol in medi- [46] Cooper JT, Stack GM, Cooper TP. Intensive medical management of
cal expulsive therapy for distal ureteral calculi. J Urol 2005;174: ureteral calculi. Urology 2000;56:575–8.
167–72. [47] Gravina GL, Costa AM, Ronchi P. Tamsulosin treatment increases
[34] Singh SK, Agarwal MM, Sharma S. Medical therapy for calculus clinical success rate of single extracorporeal shock wave lithotripsy
disease. BJU Int 2011;107:356–68. of renal stones. Urology 2005;66:24–8.
[35] Safdar B, Degutis LC, Landry K, Vedere SR, Moscovitz HC, D’Onofrio G. [48] Keshvary M, Taghavi R, Arab D. The effect of tamsulosin and
Intravenous morphine plus ketorolac is superior to either drug alone nifedipine in facilitating juxtavesical stones’ passage. Med J Mash-
for treatment of acute renal colic. Ann Emerg Med 2006;48:173–81, had University Med Sci 2006;48:425–30.
181.e1. [49] Porpiglia F, Ghignone G, Fiori C, Fontana D, Scarpa RM. Nifedipine
[36] Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal versus tamsulosin for the management of lower ureteral stones. J
function: focus on cyclooxygenase-2-selective inhibition. Am J Med Urol 2004;172:568–71.
1999;107:65–70. [50] Han MC, Jeong WS, Shim BS. Additive expulsion effect of tamsulosin
[37] Gillis JG, Brogden RN. Ketorolac: a reappraisal of its pharmacody- after shock wave lithotripsy for upper ureteral stones. Korean J Urol
namic and pharmacokinetic properties and therapeutic use in pain 2006;47:813–7.
management. Drugs 1997;53:139–88. [51] Dellabella M, Milanese G, Muzzonigro G. Medical-expulsive thera-
[38] Snir N, Moskovitz B, Nativ O, et al. Papaverine hydrochloride for the py for distal ureterolithiasis: randomized prospective study on role
treatment of renal colic: an old drug revisited. A prospective, of corticosteroids used in combination with tamsulosin-simplified
randomized study. J Urol 2008;179:1411–4. treatment regimen and health-related quality of life. Urology
[39] Roshani A, Falahatkar S, Khosropanah I, et al. Assessment of 2005;66:712–5.
clinical efficacy of intranasal desmopressin spray and diclofenac [52] Bensalah K, Pearle M, Lotan Y. Cost-effectiveness of medical expul-
sodium suppository in treatment of renal colic versus diclofenac sive therapy using alpha-blockers for the treatment of distal ure-
sodium alone. Urology 2010;75:540–2. teral stones. Eur Urol 2008;53:411–9.

You might also like