Elsevier

European Urology

Volume 56, Issue 3, September 2009, Pages 455-471
European Urology

Collaborative Review – Stone Disease
Medical Therapy to Facilitate the Passage of Stones: What Is the Evidence?

https://doi.org/10.1016/j.eururo.2009.06.012Get rights and content

Abstract

Context

Medical expulsive therapy (MET) for urolithiasis has gained increasing attention in the last years. It has been suggested that the administration of α-adrenoreceptor antagonists (α-blockers) or calcium channel blockers augments stone expulsion rates and reduces colic events.

Objective

To evaluate the efficacy and safety of MET with α-blockers and calcium channel blockers for upper urinary tract stones with and without prior extracorporeal shock wave lithotripsy (ESWL).

Evidence acquisition

A systematic review of the literature was performed in Medline, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews searched through 31 December 2008 without time limit. Efficacy and safety end points were evaluated in 47 randomised, controlled trials assessing the role of MET. Meta-analysis was conducted using Review Manager (RevMan) v.5.0 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).

Evidence synthesis

Pooling of α-blocker and calcium channel blocker studies demonstrated a higher and faster expulsion rate compared to a control group (risk ratio [RR]: 1.45 vs 1.49; 95% confidence interval [CI]: 1.34–1.57 vs 1.33–1.66). Similar results have been obtained after ESWL (RR: 1.29 vs 1.57; 95% CI: 1.16–1.43 vs 1.21–2.04). Additionally, lower analgesic requirements, fewer colic episodes, and fewer hospitalisations were observed within treatment groups.

Conclusions

Pooled analyses suggest that MET with α-blockers or calcium channel blockers augments stone expulsion rates, reduces the time to stone expulsion, and lowers analgesia requirements for ureteral stones with and without ESWL for stones ≤10 mm. There is some evidence that a combination of α-blockers and corticosteroids might be more effective than treatment with α-blockers alone. Renal stones after ESWL also seem to profit from MET. The vast majority of randomised studies incorporated into the present systematic review are small, single-centre studies, limiting the strength of our conclusions. Therefore, multicentre, randomised, placebo-controlled trials are needed.

Introduction

The simplest approach to medical expulsion therapy (MET) would be a high fluid intake to increase the hydrostatic pressure proximal to the stone or to increase the volume of urine transported through the ureter, thereby increasing peristaltic activity. The drawback is that it cannot easily be predicted to what extent a ureteral stone obstructs urine flow. In the case of partial or incomplete obstruction, constantly or intermittently, high diuresis is likely to counteract the passage of the stone and 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 [1].

An improved understanding of ureteral physiology has led to anti-inflammatory and anti-oedematous treatment with nonsteroidal anti-inflammatory drugs (NSAID) such as nonselective cyclooxygenase (COX) inhibitors or COX-2 inhibitors, decreasing ureteral contractions [2]. However, they appeared not to affect stone expulsion rates in double-blind, placebo-controlled trials [3], [4].

Antimuscarinics might relax genitourinary smooth muscle, reducing colic pain [5]. However, a randomised, placebo-controlled trial determining whether N-butylscopolamine (Buscopan) reduces the amount of opioid analgesia required in renal colic demonstrated no favourable effect [6]. Additionally, N-butylscopolamine failed to significantly reduce renal pelvic pressure [7] and was less effective than dipyrone. So far, those regimens have failed to demonstrate an increase in stone expulsion rates.

Phosphodiesterase (PDE) regulates intracellular cyclic nucleotide turnover, influencing smooth muscle tension. Recently, the ureteral smooth muscle relaxing effects of PDE type 4 inhibitor (PDE4-I) and PDE type 5 inhibitor (PDE5-I) in vitro have been reported. Results were similar to those reported for tamsulosin, suggesting the potential for using PDE inhibitors in the treatment of ureteral colic [8], [9], but so far, their potential role in expulsion therapy has to be assessed in controlled studies.

Use of corticosteroids with anti-inflammatory action has been reported to facilitate stone expulsion [10]. So far, one randomised trial (published as an abstract) supports a significant effect of methylprednisolone on distal ureteral stone expulsion [11]. However, publications in peer-reviewed journals are necessary. So far, there is no further evidence confirming whether corticosteroids alone are capable of facilitating stone expulsion.

The calcium channel blockers nifedipine and verapamil inhibit endogenous prostaglandin synthesis and calcium influx, reducing spontaneous rhythmic contractions of the human ureter [12]. Similarly, α-blockers inhibit contractions of ureteral musculature, reduce basal tone, and decrease peristaltic frequency and colic pain, possibly facilitating ureteral stone expulsion and suggesting a beneficial effect for MET. This conclusion is 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 [13]. So far, the most promising drugs studied for MET are α-blockers and calcium channel blockers, mirrored by an increasing study activity and providing the rationale for this systematic review.

Section snippets

Search strategy

The US National Library of Medicine's life science database (Medline), Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database for Systematic Reviews were searched through 31 December 2008 without time limit. The Medline search employed a search strategy that included Medical Subject Headings (MeSH) and free-text protocols. The terms urolithiasis and lithotripsy were used in conjunction with calcium-channel-blocker, adrenergic alpha-antagonists, prostaglandin

Quality assessment of studies incorporated in the final analysis

Jadad scores ranged from 0 to 5, with a median score of 2. Five double-blind studies were reported (Table 1). Allocation concealment was rarely assessable (level A was applicable to only one trial [17]) and therefore could not be integrated into the quality assessment.

α-Blocker therapy

Twenty-nine studies [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45] were analysed, including 2419

Conclusions

Evidence suggests that MET using nifedipine, tamsulosin, doxazosin, or terazosin can be suggested as treatment for ureteral stones owing to its expulsive efficacy, pain reduction, and safety profile. No recommendation can be made concerning the superiority of either nifedipine or α-blockers. Although a class effect of α-blockers can be anticipated, no recommendation can be made concerning alfuzosin. There is some evidence that a combination of α-blockers and corticosteroids might be more

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