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Medical Expulsive Therapy of Ureteral Calculi and Supportive Therapy After Extracorporeal Shock Wave Lithotripsy

  • Christian Seitz
    Correspondence
    Tel. +43 (0)699 18195333; Fax: +43 (0)1 211213552.
    Affiliations
    Department of Urology and Andrology, St. John of God, Academic Teaching Hospital of the Medical University of Vienna, Johannes von Gott Platz 1, 1020 Vienna, Austria
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      Abstract

      Context

      Medical expulsive therapy (MET) augments expulsion rates and reduces colic events. Therefore, MET is an appropriate procedure to facilitate stone passage during the observation period in patients who have a newly diagnosed ureteral stone and whose symptoms are controlled. Increasing evidence indicates that supportive therapy following shock wave lithotripsy (SWL) for urolithiasis is also effective.

      Objective

      Our aim was to summarize the literature on MET in the treatment of urolithiasis.

      Evidence acquisition

      This paper is based on a presentation given at the symposium “Terpenes in Urolithiasis” that was held in Düsseldorf, Germany, in 2010.

      Evidence synthesis

      MET with α-blockade and calcium channel blockade resulted in accelerated and higher expulsion rates compared with a control group. Higher expulsion rates were demonstrated for the entire ureter, although the vast majority of studies only included distally located stones. MET showed favorable results for renal stones after extracorporeal SWL. The number of necessary analgesic rescue medications, colic episodes, and hospital admissions during treatment periods was reduced.

      Conclusions

      MET facilitates ureteral stone passage during the observation period in patients who have a newly diagnosed ureteral stone <10 mm and whose symptoms are controlled. In patients harboring renal stones undergoing SWL, stone expulsion is augmented as well. Large-scale placebo-controlled randomized trials and the investigation of promising new substances are still needed to better define the future role of MET.

      Keywords

      1. Introduction

      Stone size, location, and symptom duration are the most important parameters to predict spontaneous stone expulsion in addition to patient-dependent factors such as pain tolerance and the development of infection that determine the need for active stone removal or decompression of the renal collecting system [
      • Hübner W.A.
      • Irby P.
      • Stoller M.L.
      Natural history and current concepts for the treatment of small ureteral calculi.
      ,
      • Miller O.F.
      • Kane C.J.
      Time to stone passage for observed ureteral calculi: a guide for patient education.
      ,
      • Dal Moro F.
      • Abate A.
      • Lanckriet G.R.
      • et al.
      A novel approach for accurate prediction of spontaneous passage of ureteral stones: support vector machines.
      ]. Miller and Kane reported the time to spontaneous stone passage of stones ≤2 mm, 2–4 mm, and 4–6 mm was an average of 8.2, 12.2, and 22.1 d, respectively, and 95% of those that passed did so by 31, 40, and 39 d, respectively [
      • Miller O.F.
      • Kane C.J.
      Time to stone passage for observed ureteral calculi: a guide for patient education.
      ]. A meta-analysis of studies in which spontaneous ureteral stone passage was assessed reported a median probability of stone passage of 68% for stones <5 mm (n = 224) and 47% for those >5 mm and <10 mm (n = 104) [
      • Preminger G.M.
      • Tiselius H.-G.
      • Assimos D.G.
      • et al.
      American Urological Association Education and Research, Inc
      European Association of Urology. 2007 guideline for the management of ureteral calculi.
      ]. These studies had certain limitations including nonstandardization of the stone size measurement methods and lack of analysis of stone position, stone-passage history, and time to stone passage. According to the European Association of Urology guidelines, observation as initial treatment is an option for patients with controlled symptoms harboring ureteral stones <10 mm.

      2. Evidence acquisition

      2.1 Ureteral pathophysiology

      An increase of cytoplasmatic free calcium concentration is one principal mechanism initiating ureteral contraction. It was demonstrated that calcium channel inhibitors counteract the phasic-rhythmic activity in isolated human caliceal segments [
      • Hertle L.
      • Nawrath H.
      Calcium channel blockade in smooth muscle of the upper urinary tract I: effects on depolarization-induced activation.
      ] and in the ureter [
      • Borghi L.
      • Meschi T.
      • Amato F.
      • et al.
      Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebo-controlled study.
      ]. Endogenous prostaglandin synthesis and calcium influx induce spontaneous rhythmic contractions of the human ureter, which are inhibited by the calcium channel blockers nifedipine and verapamil [
      • Sahin A.
      • Erdemli I.
      • Bakkaloglu M.
      • Ergen A.
      • Basar I.
      • Remzi D.
      The effect of nifedipine and verapamil on rhythmic contractions of human isolated ureter.
      ]. This negative effect on ureteral contractility has evoked interest in using calcium channel blockers to facilitate medical-induced stone passage.
      Three different subtypes of adrenergic receptors (ARs) have been pharmacologically identified: α1A, α1B, and α1D[
      • Hieble J.P.
      • Bylund D.B.
      • Clarke D.E.
      • et al.
      International Union of Pharmacology. X. Recommendations for nomenclature of alpha1-adrenoceptors: Consensus update.
      ]. A heterogeneous distribution of α1 AR binding sites was detected, with the highest density in the distal ureter [
      • Sigala S.
      • Dellabella M.
      • Milanese G.
      • et al.
      Evidence for the presence of α1 adrenoceptor subtypes in the human ureter.
      ]. The distribution of ARs throughout the inner and outer smooth muscle of the ureter was highest for α1D, especially in the distal ureter, followed by α1A and α1B ARs [
      • Itoh Y.
      • Kojima Y.
      • Yasui T.
      • Tozawa K.
      • Sasaki S.
      • Kohri K.
      Examination of alpha 1 adrenoceptor subtypes in the human ureter.
      ]. Of interest, heterodimers α1B1A and α1B1D do occur, whereas α1A1D ARs do not heterodimerize, suggesting a possible regulatory role of α1B[
      • Uberti M.A.
      • Hall R.A.
      • Minneman K.P.
      Subtype-specific dimerization of alpha 1-adrenoceptors: effects on receptor expression and pharmacological properties.
      ]. This ability to oligodimerize could influence future drug development.
      The exact pathophysiology of ureteral colic and stone passage is not completely understood. A ureteral stone tends to induce a ureteral inflammatory response by ureteral stone obstruction and ureteral wall tension stimulating prostaglandin synthesis. Prostaglandins have a dilating effect on afferent arterioles resulting in an increased renal blood flow, further increasing ureteropelvic pressure, inflammation, and edema [
      • Ahmad M.
      • Chaughtai M.N.
      • Kahn F.A.
      Role of prostaglandin synthesis inhibitors in the passage of ureteric calculus.
      ]. A subsequent increase of smooth muscle contraction impairs propulsive antegrade peristalsis aggravating ureteral obstruction, impaction, and pain [
      • Holmlund D.
      • Hassler O.
      A method of studying the ureteral reaction to artificial concrements.
      ,
      • Yamaguchi K.
      • Minei S.
      • Yamazachi T.
      • Kaya H.
      • Okada K.
      Characterization of ureteral lesions associated with impacted stones.
      ]. Therefore the ideal agent to facilitate stone expulsion would reduce ureteral inflammation, edema, ureteral spasm, and uncoordinated ureteral contractions without altering propulsive peristalsis.

      2.2 Medical expulsive therapy

      A rational approach to expulsion therapy would be to increase peristaltic activity with high fluid intake increasing the volume transported through the ureter and thereby augmenting the hydrostatic pressure above the stone. In cases of obstruction, a high diuresis is likely to counteract the passage of the stone and to cause more pain. A systematic review evaluating the effect of fluids and diuretics found no credible evidence supporting a diuretic approach in terms of pain relief and stone expulsion [
      • Worster A.
      • Richards C.
      Fluids and diuretics for acute ureteric colic.
      ]. A recent randomized comparison between high and normal diuresis during the primary session of shock wave lithotripsy (SWL) for removal of ureteral stones did not demonstrate a beneficial effect [
      • Tiselius H.G.
      • Aronsen T.
      • Bohgard S.
      • et al.
      Is high diuresis an important prerequisite for successful SWL-disintegration of ureteral stones?.
      ].
      An improved understanding of ureteral physiology has led to an anti-inflammatory and antiedematous treatment by nonsteroidal anti-inflammatory drugs (NSAIDs), decreasing agonist-induced contractions in pig ureters [
      • Mastrangelo D.
      • Wisard M.
      • Rohner S.
      • Leisinger H.
      • Iselin C.E.
      Diclofenac and NS-398, a selective cyclooxygenase-2 inhibitor, decrease agonist induced contractions of the pig isolated ureter.
      ]. Cyclooxygenase (COX)-2 inhibitors were able to inhibit prostanoid release and ureteral contractility [
      • Jerde T.J.
      • Calamon-Dixon J.L.
      • Bjorling D.E.
      • Nakada S.Y.
      Celecoxib inhibits ureteral contractility and prostanoid release.
      ]. NSAIDs have proved effective by inhibiting prostanoid synthesis and reducing vasodilatation with subsequent reduction of inflammation, glomerular filtration rate, and intrarenal pressure [
      • Ahmad M.
      • Chaughtai M.N.
      • Kahn F.A.
      Role of prostaglandin synthesis inhibitors in the passage of ureteric calculus.
      ]. However, stone expulsion rates were not affected in double-blind placebo-controlled trials [
      • Laerum E.
      • Ommundsen O.E.
      • Grønseth J.E.
      • Christiansen A.
      • Fagertun H.E.
      Oral diclofenac in the prophylactic treatment of recurrent renal colic. A double-blind comparison with placebo.
      ,
      • Phillips E.
      • Hinck B.
      • Pedro R.
      • et al.
      Celecoxib in the management of acute renal colic: a randomized controlled clinical trial.
      ].
      Terpenes were reported to have diuretic anti-inflammatory analgesic and spasmolytic properties. Among the reported properties the anti-inflammatory effect is achieved by the suppression of arachidonic acid metabolism and cytokine production [
      • Lee C.B.
      • Ha U.S.
      • Lee S.J.
      • Kim S.W.
      • Cho Y.H.
      Preliminary experience with a terpene mixture versus ibuprofen for treatment of category III chronic prostatitis/chronic pelvic pain syndrome.
      ]. In a prospective randomized placebo-controlled single-blind trial for prostatitis/chronic pelvic pain syndrome, Rowatinex demonstrated more improvement in the numerical value for pain score than ibuprofen [
      • Lee C.B.
      • Ha U.S.
      • Lee S.J.
      • Kim S.W.
      • Cho Y.H.
      Preliminary experience with a terpene mixture versus ibuprofen for treatment of category III chronic prostatitis/chronic pelvic pain syndrome.
      ]. Rowatinex was reported in recent randomized controlled trials (RCTs) to accelerate stone-free rates and reduce symptoms during stone passage in patients undergoing SWL for renal stones. No significant adverse events leading to discontinuation of the drug were reported [
      • Djaladat H.
      • Mahouri K.
      • Khalifeh Shooshtary F.
      • Ahmadieh A.
      Effect of Rowatinex on calculus clearance after extracorporeal shock wave lithotripsy.
      ]. Rowatinex will continue to be evaluated in the medical treatment of upper urinary stone disease.
      Another potent analgesic and antipyretic drug that has been proposed to inhibit COX enzyme activity is dipyrone. Studies in animal and human ureters demonstrated a significant reduction of renal pelvic pressure with dipyrone and the NSAID indomethacin that alleviated colic pain [
      • Zwergel U.
      • Felgner J.
      • Rombach H.
      • Zwergel T.H.
      Aktuelle konservative Behandlung einer Nierenkolik: Stellenwert der Prostaglandinsynthesehemmer.
      ]. Holmlund and Sjödin had already shown the effect of indomethacin in 1978 [
      • Holmlund D.
      • Sjödin J.G.
      Treatment of ureteral colic with indomethacin.
      ]. However, so far no study has reported an accelerated stone expulsion.
      Antimuscarinics might relax genitourinary smooth muscle and thus reduce colic pain [
      • Schneider T.
      • Fetscher C.
      • Krege S.
      • Michel M.C.
      Signal transduction underlying carbachol-induced contraction of human urinary bladder.
      ]. However, a randomized placebo-controlled trial determining whether N-butylscopolamine (Buscopan) reduces the amount of opioid analgesia required in renal colic showed no favorable effect [
      • Holdgate A.
      • Pollock T.
      Systematic review of the relative efficacy of non-steroidal anti-inflammatory drugs and opioids in the treatment of acute renal colic.
      ]. N-butylscopolamine failed to reduce renal pelvic pressure significantly [
      • Zwergel U.
      • Felgner J.
      • Rombach H.
      • Zwergel T.H.
      Aktuelle konservative Behandlung einer Nierenkolik: Stellenwert der Prostaglandinsynthesehemmer.
      ] and was less effective than dipyrone. The addition of spasmolytic agents (eg, hyoscine) to dipyrone did not improve its analgesic efficacy [
      • Edwards J.E.
      • Meseguer F.
      • Faura C.
      • Moore R.A.
      • McQuay H.J.
      Single dose dipyrone for acute renal colic pain.
      ]. Those regimens have failed so far to demonstrate an increase in stone expulsion rates, but it might be interesting to explore the effects further in randomized studies.
      Phosphodiesterases (PDEs) regulate intracellular cyclic nucleotide turnover influencing smooth muscle tension. Kühn et al found relaxing effects on potassium chloride–induced tension of ureteral smooth muscle by PDE4 and PDE5 inhibitors in vitro [
      • Kühn R.
      • Ückert S.
      • Stief C.G.
      • et al.
      Relaxation of human ureteral smooth muscle in vitro by modulation of cyclic nucleotide-dependent pathways.
      ]. Gratzke et al demonstrated the ureteral smooth muscle relaxing effects of different PDE5 inhibitors in vitro. Results were similar to those reported for tamsulosin, suggesting the potential of using PDE inhibitors in the treatment of ureteral colic [
      • Gratzke C.
      • Ückert S.
      • Reich O.
      • et al.
      PDE-5-Inhibitoren: Ein neuer Therapieansatz in der Behandlung der Harnleiterkolik?.
      ]. Another drug that interferes with the PDE enzyme is papaverine, which results in an increase of adenosine monophosphate that causes ureteral smooth muscle relaxation. Its analgesic potential is similar to that of pethidine and diclofenac, and its superiority to hyoscine butylbromide was demonstrated in recent randomized trials [
      • Snir N.
      • Moskovitz B.
      • Nativ O.
      • et al.
      Papaverine hydrochloride for the treatment of renal colic: an old drug revisited—a prospective randomized study.
      ,
      • Yencilek F.
      • Aktas C.
      • Goktas C.
      • Yilmaz C.
      • Yilmaz U.
      • Sarica K.
      Role of papaverine hydrochloride administration in patients with intractable renal colic: randomized prospective trial.
      ]. Further studies are necessary to assess their potential role in expulsion therapy.
      Corticosteroids have been reported to facilitate stone expulsion [
      • Mikkelsen A.L.
      • Meyhoff H.H.
      • Lindahl F.
      • Christensen J.
      The effect of hydroxyprogesterone on ureteral stones.
      ,
      • Salehi M.
      • Fouladi Mehr M.
      • Shiery H.
      • et al.
      Does methylprednisolone acetate increase the success rate of medical therapy for passing distal ureteral stones?.
      ]. However, publications in peer-reviewed journals are necessary. So far no further evidence has confirmed whether corticosteroids alone are capable of facilitating stone expulsion.
      α-Adrenoreceptor antagonists (α-blockers) inhibit contractions of ureteral musculature, reduce the basal tone, and decrease peristaltic frequency and colic pain facilitating ureteral stone expulsion. Davenport et al found a beneficial effect of both nifedipine and 5-methylurapidil on human ureteric activity with a median reduction in proximal versus distal ureteral tone of 47% versus 57% and 33% versus 65%, respectively [
      • Davenport K.
      • Timoney A.
      • Keeley F.X.
      Effect on smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study.
      ]. These data suggest a beneficial effect for MET further supported by a pilot study investigating the in vivo effect of nifedipine and tamsulosin on ureteral contraction frequency, pressure, and velocity using a ureteric pressure transducer in humans. Both drugs allowed peristalsis to continue, which is important for successful stone expulsion [
      • Davenport K.
      • Timoney A.
      • Keeley F.X.
      A comparative in vitro study to determine the beneficial effect of calcium-channel and alpha (1)-adrenoceptor antagonism on human ureteric activity.
      ].

      3. Evidence synthesis

      A recent meta-analysis offered evidence for an overall increased stone expulsion rate and reduced time to stone expulsion using an α-blocker or calcium channel blocker compared with a standard therapy or placebo control group (Fig. 1) [
      • Seitz C.
      • Liatsikos E.
      • Porpiglia F.
      • Tiselius H.-G.
      • Zwergel U.
      Medical therapy to facilitate the passage of stones: what is the evidence?.
      ]. A class effect for α-blockers was suggested after similar expulsion rates for tamsulosin, terazosin, and doxazosin were observed [
      • Yilmaz E.
      • Batislam E.
      • Basar M.M.
      • Tuglu D.
      • Ferhat M.
      • Basar H.
      The comparison and efficacy of 3 different α1-adrenergic blockers for distal ureteral stones.
      ]. Similar results were obtained using terazosin, doxazosin, and the α1-blocker naftopidil, further confirming the concept of a class effect [
      • Ukhal M.I.
      • Malomuzh O.I.
      • Strashny V.
      Administration of doxazosin for speedy elimination of stones from lower section of ureter.
      ,
      • Mohseni M.G.
      • Hosseini S.R.
      • Alizadeh F.
      Efficacy of terazosin as a facilitator agent for expulsion of the lower ureteral stones.
      ,
      • Ayubov B.
      • Arustamov D.
      • Mukhtarov S.
      Efficacy of doxazosin in the management of ureteral stones.
      ,
      • Liatsikos E.N.
      • Katsakiori P.F.
      • Assimakopoulos K.
      • et al.
      Doxazosin for the management of distal-ureteral stones.
      ,
      • Mukhtarov S.
      • Turdiev A.
      • Fozilov A.
      • et al.
      Using doxazosin for distal ureteral stone clearance with or without shock wave lithotripsy.
      ,
      • Sun X.
      • He L.
      • Ge W.
      • Lv J.
      Efficacy of selective alpha1D-blocker naftopidil as medical expulsive therapy for distal ureteral stones.
      ]. Only one alfuzosin trial reported an inferior numerical outcome for the treatment group [
      • Pedro R.N.
      • Hinck B.
      • Hendlin K.
      • Feia K.
      • Canales B.K.
      • Monga M.
      Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study.
      ]. However, the time to stone expulsions and pain scores were significantly in favor of the treatment group.
      Figure thumbnail gr1
      Fig. 1Forest plot of comparison: α-blockade versus control; outcome: stone free. Risk ratios (RRs) in each square with area proportional to the number of events comparing outcome in patients allocated to an α-blocker group with outcome in patients allocated to a control group, along with 95% confidence intervals (CIs) as the horizontal line. Overall RRs and CIs are plotted as a diamond. A square or diamond to the right of the vertical line of no effect indicates a benefit with α-blockers. This benefit is significant (p < 0.05) only if the horizontal line or diamond does not overlap the vertical line. Adapted from Seitz et al.
      [
      • Seitz C.
      • Liatsikos E.
      • Porpiglia F.
      • Tiselius H.-G.
      • Zwergel U.
      Medical therapy to facilitate the passage of stones: what is the evidence?.
      ]
      .
      M-H = Mantel-Haenszel test.

      3.1 Stone size and medical expulsion therapy

      Due to the high likelihood of spontaneous passage for stones up to about 4 mm, one would expect that the efficacy for medical expulsion therapy (MET) would decrease because of the high spontaneous expulsion rate.
      Of interest, three high-quality double-blinded RCTs failed to demonstrate a significant higher expulsion rate for MET using alfuzosin or tamsulosin [
      • Pedro R.N.
      • Hinck B.
      • Hendlin K.
      • Feia K.
      • Canales B.K.
      • Monga M.
      Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study.
      ,
      • Vincendeau S.
      • Bellissant E.
      • Bansalah K.
      • et al.
      Lack of efficacy of tamsulosin in the treatment of distal ureteral stones.
      ,
      • Hermanns T.
      • Sauermann P.
      • Rufibach K.
      • Frauenfelder T.
      • Sulser T.
      • Strebel R.T.
      Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial.
      ]. In addition to a possible lower effectiveness of alfuzosin, a small mean stone size of 3.8 mm could have accounted for high spontaneous stone passage rates leading to an underestimation of alfuzosin in promoting stone passage [
      • Pedro R.N.
      • Hinck B.
      • Hendlin K.
      • Feia K.
      • Canales B.K.
      • Monga M.
      Alfuzosin stone expulsion therapy for distal ureteral calculi: a double-blind, placebo controlled study.
      ]. The same applies for the study of Vincendeau et al including distal ureteral stones with a mean stone size of 2.9 mm and 3.2 mm for the treatment and control groups, respectively [
      • Vincendeau S.
      • Bellissant E.
      • Bansalah K.
      • et al.
      Lack of efficacy of tamsulosin in the treatment of distal ureteral stones.
      ]. In the study from Hermanns et al. [
      • Hermanns T.
      • Sauermann P.
      • Rufibach K.
      • Frauenfelder T.
      • Sulser T.
      • Strebel R.T.
      Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial.
      ], 76% and 84% of the patients in the tamsulosin and control groups harbored distal ureteral stones <5 mm. Tamsulosin did not improve expulsion rates in stones >5 mm (Table 1). However, as the authors stated, the study was not powered for this subgroup analysis [
      • Hermanns T.
      • Sauermann P.
      • Rufibach K.
      • Frauenfelder T.
      • Sulser T.
      • Strebel R.T.
      Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial.
      ]. Although the limited numbers of patients might account for the undetectable significant differences in the treatment of smaller stones, results might as well indicate that with decreasing stone size an additional benefit for MET is less likely owing to the high spontaneous expulsion rate. Nevertheless, a numerically accelerated expulsion rate and significant analgesic effect within the treatment group was observed [
      • Hermanns T.
      • Sauermann P.
      • Rufibach K.
      • Frauenfelder T.
      • Sulser T.
      • Strebel R.T.
      Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial.
      ]. Similarly, Ferre et al failed to demonstrate a significant higher expulsion rate in the tamsulosin group. Again, mean stone size was 3.6 mm [
      • Ferre R.M.
      • Wasielewski J.N.
      • Strout T.D.
      • Perron A.D.
      Tamsulosin for ureteral stones in the emergency department: a randomized controlled trial.
      ]. However, the “ideal” stone size for MET is not known. It is reasonable to assume that the stone expulsion rate of MET will be greatest somewhere between 4 and 10 mm.
      Table 1Efficacy and safety data from recent randomized controlled trials at different formulations for medical expulsive therapy
      ReferenceBlindedPower calculatedAnalgesic therapyTreatment vs controlExpulsion rate/Sample size (%)p valueSize range/locationSize mean¥ medianp valueExpulsion time, d (%)p valueAnalgesic dosagep valueAdverse events leading to cessationStudy duration, d
      Al-Ansari et al, 2010DoubleYesDiclofenac 75 mgTamsulosin 0.4 mg

      Placebo
      41/50 (82)

      28/46 (61)
      0.02<10 mm

      Distal ureter
      5.9

      6.0
      NS6.4

      9.9
      <0.0568 mg

      127 mg
      0.001None28
      Ferre et al, 2009
      • Ferre R.M.
      • Wasielewski J.N.
      • Strout T.D.
      • Perron A.D.
      Tamsulosin for ureteral stones in the emergency department: a randomized controlled trial.
      NoYesIbuprofen plus

      oxycodone
      Tamsulosin 0.4 mg

      ControlΩ
      27/35 (77.1)

      24/37 (64.9)
      NS<10 mm

      Distal ureter
      3.6¥NSNSXNSNone14
      Griwan et al,

      2010
      NoNoDiclofenac 50 mgTamsulosin 0.4 mg

      Control
      27/30 (90)

      21/30 (70)


      0.04
      4–10 mm

      Distal ureter

      6.3¥

      6.7*
      NS7 (50)

      7 (27)
      0.00130 mg

      63 mg


      0.007


      None
      28
      Hermanns et al,

      2009
      • Hermanns T.
      • Sauermann P.
      • Rufibach K.
      • Frauenfelder T.
      • Sulser T.
      • Strebel R.T.
      Is there a role for tamsulosin in the treatment of distal ureteral stones of 7 mm or less? Results of a randomised, double-blind, placebo-controlled trial.
      DoubleYesTamsulosin 0.4 mg

      Placebo
      39/45 (86.7)

      40/45 (88.9)
      NS≤7 mm

      Distal ureter
      4.1

      3.8
      NS7

      10
      NS3

      7 units
      0.011121
      Kanekoet et al,

      2010
      NoNoDiclofenac 50 mgTamsulosin 0.2 mg

      Control
      24/31 (77)

      17/34 (50)
      0.002X

      Proximal plus distal ureter
      4.6

      4.8
      NS14

      17
      NS0.50

      0.47 units
      NSNone28
      Sun et al,

      2009
      • Sun X.
      • He L.
      • Ge W.
      • Lv J.
      Efficacy of selective alpha1D-blocker naftopidil as medical expulsive therapy for distal ureteral stones.
      NoYesIndomethacin supplementNaftopidil 50 mg

      Control
      27/30 (90)

      8/30 (27)
      0.0014–15 mm

      Distal ureter

      5.7

      5.5
      NS7

      6
      NSNone14
      Zehri et al,

      2010
      NoYesDiclofenac 50 mgDoxazosin 2 mg

      Control
      23/33 (70)

      12/32 (38)
      0.0094–7 mm

      Distal ureter
      5.3

      *5.5*
      NS7

      12.5
      0.0057

      16

      units
      0.005None28
      NS = not significant.

      3.2 Tamsulosin versus nifedipine in medical expulsion therapy

      Three studies compared the efficacy of tamsulosin compared with nifedipine for distal ureteral stones [
      • Keshvary M.
      • Taghavi R.
      • Arab D.
      The effect of tamsulosin and nifedipine in facilitating juxtavesical stones’ passage.
      ,
      • Porpiglia F.
      • Ghignone G.
      • Fiori C.
      • Fontana D.
      • Scarpa R.M.
      Nifedipine versus tamsulosin for the management of lower ureteral stones.
      ,
      • Dellabella M.
      • Milanese G.
      • Muzzonigro G.
      Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi.
      ]. Keshvary et al found no statistical difference in expulsion rates between tamsulosin and nifedipine [
      • Keshvary M.
      • Taghavi R.
      • Arab D.
      The effect of tamsulosin and nifedipine in facilitating juxtavesical stones’ passage.
      ]. Porpiglia et al evaluated the effectiveness of tamsulosin versus nifedipine in combination with deflazacort for stones <10 mm. Expulsion rates and expulsion time were in favor of the tamsulosin group, although differences were not significant [
      • Porpiglia F.
      • Ghignone G.
      • Fiori C.
      • Fontana D.
      • Scarpa R.M.
      Nifedipine versus tamsulosin for the management of lower ureteral stones.
      ]. Dellabella et al compared the efficacy of tamsulosin and nifedipine in combination with deflazacort for stones >4 mm and found a significantly higher expulsion rate (p = 0.001) and shorter expulsion time (p < 0.0001) in the tamsulosin group, although stones in the tamsulosin group were significantly larger (7.2 vs 6.2 mm). Notably, stone size and expulsion time did not correlate, a finding that might be attributable to the concomitant administration of a corticosteroid [
      • Dellabella M.
      • Milanese G.
      • Muzzonigro G.
      Randomized trial of the efficacy of tamsulosin, nifedipine and phloroglucinol in medical expulsive therapy for distal ureteral calculi.
      ]. Hospitalizations, loss of workdays, auxiliary measures, and the amount of rescue medication were significantly in favor of the tamsulosin group.

      3.3 Shock wave lithotripsy and medical expulsion therapy

      It would be reasonable to assume that MET is effective after SWL for renal stones because the fragments have to pass the ureter. Pooled data for α-blocker after SWL suggested a treatment benefit for ureteral stones [
      • Seitz C.
      • Liatsikos E.
      • Porpiglia F.
      • Tiselius H.-G.
      • Zwergel U.
      Medical therapy to facilitate the passage of stones: what is the evidence?.
      ]. All tamsulosin 0.4 mg, doxazosin, and terazosin trials demonstrated a treatment benefit, suggesting a class effect. Colic episodes or analgesic doses in the α-blocker groups were significantly lower in six [
      • Mukhtarov S.
      • Turdiev A.
      • Fozilov A.
      • et al.
      Using doxazosin for distal ureteral stone clearance with or without shock wave lithotripsy.
      ,
      • Gravas S.
      • Tzortzis V.
      • Karatzas A.
      • Oeconomou A.
      • Melekos M.D.
      The use of tamsulosin as adjunctive treatment after ESWL in patients with distal ureteral stone: do we really need it? Results from a randomised study.
      ,
      • Gravina G.L.
      • Costa A.M.
      • Ronchi P.
      Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones.
      ,
      • Han M.C.
      • Park Y.Y.
      • Shim B.S.
      Effect of tamsulosin on the expectant treatment of lower ureteral stones.
      ,
      • Resim S.
      • Ekerbicer H.C.
      • Ciftci A.
      Role of tamsulosin in treatment of patients with steinstrasse developing after extracorporeal shock wave lithotripsy.
      ,
      • Shaaban Alaa M.
      • Barsoum Nady M.
      • Sagheer Gamal A.
      • Ahmed Z.
      Is there a role for alpha blocker after SWL for renal and upper ureteral stones?.
      ] of seven trials. Only one tamsulosin 0.2 mg trial after extracorporeal shock wave lithotripsy (ESWL) reported unfavorable outcomes for the treatment group, although differences were not significant. Nevertheless, the mean time to stone expulsion was significantly in favor of the treatment group (15.7 ± 6.1 vs 35.5 ± 53.7; p = 0.04) [
      • Kobayashi M.
      • Naya Y.
      • Kino M.
      Low dose tamsulosin for stone expulsion after extracorporeal shock wave lithotripsy: efficacy in Japanese male patients with ureteral stone.
      ].
      Four studies available for renal stones treated with ESWL showed a beneficial effect for α-blockade [
      • Gravina G.L.
      • Costa A.M.
      • Ronchi P.
      Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones.
      ,
      • Bhagat S.K.
      • Chacko N.K.
      • Kekre N.S.
      • Gopalakrishnan G.
      • Antonisamy B.
      • Devasia A.
      Is there a role for tamsulosin in shock wave lithotripsy for renal and ureteral calculi?.
      ,
      • Naja V.
      • Agarwal M.M.
      • Mandal A.K.
      • et al.
      Tamsulosin facilitates earlier clearance of stone fragments and reduces pain after shockwave lithotripsy for renal calculi: results from an open-label randomized study.
      ,
      • Hussein M.M.
      Does tamsulosin increase stone clearance after shockwave lithotripsy of renal stones? A prospective, randomized controlled study.
      ]. Additionally, the double-blind RCT from Romics et al also demonstrated a significant higher expulsion rate and decreased expulsion time with a special combination of terpenes (Rowatinex) after ESWL [
      • Romics I.
      • Siller G.
      • Kohnen R.
      • Mavrogenis S.
      • Varga J.
      • Holman E.
      Improving stone clearance after extracorporeal shock wave lithotripsy in urolithiasis patients by a special terpene combination (Rowatinex®): results of a placebo-controlled, randomized trial.
      ]. This is discussed in detail elsewhere in this supplement. α-Blockers also could prove beneficial for proximal ureteral stone locations because they mediate a reduction in proximal ureteral tone of 33% [
      • Davenport K.
      • Timoney A.
      • Keeley F.X.
      Effect on smooth muscle relaxant drugs on proximal human ureteric activity in vivo: a pilot study.
      ]. All fragments have to pass the distal ureter; therefore, stone passage might be facilitated with decreased expulsion time and fewer colicky episodes. Indeed, findings suggest a beneficial effect. Han et al administered tamsulosin for upper ureteral stones after ESWL and found a significant increased expulsion rate and significant decreased analgesic requirements versus a control group [
      • Han M.C.
      • Jeong W.S.
      • Shim B.S.
      Additive expulsion effect of tamsulosin after shock wave lithotripsy for upper ureteral stones.
      ]. Porpiglia et al demonstrated a relatively higher expulsion rate for upper ureteral stones compared with a control group using nifedipine in conjunction with a corticosteroid. The expulsion rate in the treatment group was equal for upper and distal ureteral stones [
      • Porpiglia F.
      • Destefanis P.
      • Fiori C.
      • Scarpa R.M.
      • Fontana D.
      Role of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stones.
      ]. However, one single-centre nonblinded RCT including <15 mm proximal ureteral stones failed to demonstrate a significant treatment effect after SWL [
      • Agarwal M.M.
      • Naja V.
      • Singh S.K.
      • et al.
      Is there an adjunctive role of tamsulosin to extracorporeal shockwave lithotripsy for upper ureteric stones: results of an open label randomized nonplacebo controlled study.
      ].
      Similar to patients undergoing MET, stone size could also influence the efficacy of MET after SWL. Observations from SWL studies suggested an adjunct role of α-blocker to ESWL. Gravina et al and Bhagat et al found no significant difference in stone-free rates in 6- to 10-mm ureteral stones but with increasing stone size of ≥11 mm the difference became significant [
      • Gravina G.L.
      • Costa A.M.
      • Ronchi P.
      Tamsulosin treatment increases clinical success rate of single extracorporeal shock wave lithotripsy of renal stones.
      ,
      • Bhagat S.K.
      • Chacko N.K.
      • Kekre N.S.
      • Gopalakrishnan G.
      • Antonisamy B.
      • Devasia A.
      Is there a role for tamsulosin in shock wave lithotripsy for renal and ureteral calculi?.
      ]. Similar findings were reported by Küpeli et al. [
      • Küpeli B.
      • Irkilata L.
      • Gürocak S.
      • et al.
      Does tamsulosin enhance lower ureteral stone clearance with or without shock wave lithotripsy?.
      ]. The difference in expulsion rates between treatment and control groups for stones <5 mm was not significant. In contrast, stone-free rates in patients treated for stones >5 mm were significantly in favor of the treatment group. In patients receiving nifedipine after ESWL, Porpiglia et al demonstrated that the average stone size of the stone-free versus non–stone-free patients was not significantly different (11.8 vs 11.4 mm). In contrast, average stone size in stone-free versus non–stone-free patients in the control group was significantly different (8.8 vs 11.5 mm; p = 0.002), suggesting facilitated stone passage for larger stones in the nifedipine group [
      • Porpiglia F.
      • Destefanis P.
      • Fiori C.
      • Scarpa R.M.
      • Fontana D.
      Role of adjunctive medical therapy with nifedipine and deflazacort after extracorporeal shock wave lithotripsy of ureteral stones.
      ].

      3.4 Adverse events in medical expulsion therapy

      Adverse events (AEs) rarely led to dropouts of patients and were reversible after discontinuation of the drug. Dropout rates might have been low in trials with previous exclusion of patients prone to side effects of the drugs used (eg, hypotensive patients) [
      • Borghi L.
      • Meschi T.
      • Amato F.
      • et al.
      Nifedipine and methylprednisolone in facilitating ureteral stone passage: a randomized, double-blind, placebo-controlled study.
      ,
      • Porpiglia F.
      • Ghignone G.
      • Fiori C.
      • Fontana D.
      • Scarpa R.M.
      Nifedipine versus tamsulosin for the management of lower ureteral stones.
      ,
      • Porpiglia F.
      • Destefanis P.
      • Fiori C.
      • Fontana D.
      Effectiveness of nifedipine and deflazacort in the management of distal ureter stones.
      ]. Inclusion of various drugs for standard treatment or steroids added to the treatment group possibly accounted for additional AEs, although a 10-d course of corticosteroids seems to be only associated with a low AE profile.

      3.5 Cost effectiveness of medical expulsion therapy

      Bensalah et al conducted an elaborate evaluation of the cost effectiveness of MET compared with conservative therapy for distal ureteral stones in five countries [
      • Bensalah K.
      • Pearle M.
      • Lotan Y.
      Cost-effectiveness of medical expulsive therapy using alpha-blockers for the treatment of distal ureteral stones.
      ]. Calculations were based on the pooled risk ratio (RR) for treatment with an α-blocker (RR: 1.54; 95% confidence interval, 1.29–1.85) reported by Hollingsworth et al. [
      • Hollingsworth J.M.
      • Rogers M.A.
      • Kaufman S.R.
      • et al.
      Medical therapy to facilitate urinary stone passage: a meta-analysis.
      ]. It was assumed that failures underwent ureterorenoscopy, which was shown to be more cost effective than ESWL for ureteral stone treatment of any location in most of the countries investigated including the United States [
      • Lotan Y.
      • Cadeddu J.A.
      • Paerle M.S.
      International comparison of cost effectiveness of medical management strategies for nephrolithiasis.
      ]. However, obvious but inevitable limitations of any cost analysis are intra- and international variations in the degree of reimbursement and subsidization of services and pharmaceutical costs.

      4. Conclusions

      In a patient who has a newly diagnosed ureteral stone <10 mm and whose symptoms are controlled, observation with periodic evaluation is an option. Patients may be offered an appropriate MET to facilitate stone passage. There is evidence that MET reduces additional analgesic requirements and accelerates the spontaneous passage of ureteral stones <10 mm as well as renal stone fragments generated with SWL. With decreasing stone size, an increased stone-free rate after MET is less likely because of the high spontaneous expulsion rate. Evidence suggests that MET can be suggested as an effective treatment option. However, large-scale placebo-controlled RCTs and the investigation of promising new substances is still needed to better define the future and optimized role of MET.

      Conflicts of interest

      In recent years, the author has received consultancy or lecturer honoraria from Rowa Pharmaceuticals.

      Funding support

      None.

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