Agent class
Drugs in class reported in MET studies
Proposed mechanism of action
Safety in pregnancy
Potential side effectsa
Selective COX inhibitors
Celecoxib
Inhibition of COX-2 enzymes, reduction of ureteral contractility
Class C (risk cannot be ruled out) amay cause premature closure of the fetal patent ductus arteriosus
GI: upset, ulcers/bleeding
Renal: ↓renal blood flow, renal insufficiency
CV: ↑risk of MI and stroke, hypertension
NSAIDs/Non-selective COX inhibitors
Indomethacin, ibuprofen, diclofenac
Inhibition of COX-1 and 2 enzymes, reduction of ureteral contractility
Class C (risk cannot be ruled out) amay cause premature closure of the fetal patent ductus arteriosus
GI: upset, ulcers/bleeding
Renal: ↓ renal blood flow, renal insufficiency
CV: ↑risk of MI and stroke, hypertension
Steroids
Methylprednisolone, deflazacort, prednisone
Anti-inflammatory, reduction of ureteral edema
Class C (risk cannot be ruled out)
CV: arrhythmias, thromboembolism
CNS: emotional disturbance
Endocrine: adrenal suppression, hyperglycemia
GI: hemorrhage, ulcer, ↑transaminases
Misc: leukocytosis, osteoporosis, impaired wound healing, cataracts, aseptic joint necrosis, infections
Calcium-channel blockers
Nifedipine
Calcium channel blockade impairs depolarization of smooth muscle cells in ureter, promoting relaxation
Class C (risk cannot be ruled out)
CV: flushing, edema, palpitations, hypotension
CNS: dizziness, headache, fatigue
GI: nausea
Alpha-blockers
Tamsulosin, doxazosin, terazosin, silodosin
Alpha adrenergic receptor blockade, ureteral smooth muscle relaxation, ↓ureteral peristalsis
Tamsulosin, alfuzosin and silodosin: Class B (adverse events not observed in animal reproduction studies) athese drugs are not FDA-labeled for use in women
CV: orthostatic hypotension
Doxazosin and terazosin: Class C (risk cannot be ruled out)
CNS: headache, dizziness, fatigue
ENT: rhinitis, Intraoperative Floppy Iris Syndrome
GU: Abnormal ejaculation
Anticholinergics
Tolteridine, oxybutynin
Smooth muscle relaxation via muscarinic receptors
Oxybutynin: Class B (adverse events not observed in animal reproduction studies)
CV: hypertension
Tolteridine: Class C (risk cannot be ruled out)
CNS: cognitive changes, especially in elderly
ENT: dry mucous membranes, glaucoma
GI: constipation
GU: urinary retention
In 2002, Cervenakov and colleagues published the first study of alpha antagonists as medical expulsive therapy to appear in the literature [21]. In this double-blinded study, the investigators randomized 104 patients with distal ureteral stones to standard therapy or standard therapy plus tamsulosin 0.4 mg daily. While no statistical analysis was done, the authors reported improved stone passage rates in the group receiving tamsulosin (80 % vs. 63 %), as well as faster stone passage. These findings prompted further investigations into these agents.
Since that time, dozens of studies on the effect of alpha blockers on stone passage have appeared in the literature, too many to individually review here. The abundance of investigations has allowed several meta-analyses to be conducted, summarizing the findings of these studies. The outcomes of these meta-analyses can be found in Table 5.2. The first meta-analysis published was by Hollingsworth and colleagues in 2006 [22]. When the authors excluded studies in which patients also received either steroids or benzodiazepines, they calculated that alpha blockers were associated with a 54 % increase in stone passage compared to control (RR 1.54; P < 0.001; 95 % CI 1.29–1.85).
Table 5.2
Published meta-analyses of alpha-blocker agents for medical expulsive therapy
Study/year published | # Studies included | # Patients included | Alpha-blockers included | Effect on stone passage rates | Effect on time to stone passage | Additional findings |
|---|---|---|---|---|---|---|
Hollingsworth 2006 [22] | 5 | a | Tamsulosin, doxazosin, terazosin (steroids and benzodiazepines excluded) | Alpha blockers improved rates of stone passage (RR 1.54; P < 0.001; 95 % CI 1.29–1.85) | NR (data not pooled) | |
Preminger 2007 [4] | 6 | 280 | Tamsulosin, doxazosin, terazosin (potentially confounding agents in included studies: steroids) | 29 % absolute increase in stone passage rates with alpha blockers | NR | |
Singh 2007 [50] | 16 | 1,235 | Tamsulosin (13/16), doxazosin, terazosin (potentially confounding agents in included studies: steroids, anticholinergics) | Alpha-blockers improved rates of stone passage (RR 1.59; 95 % CI 1.44–1.75) | NR | Adverse events reported in 4 % of participants |
Seitz 2009 [51] | 29 | 2,419 | Tamsulosin, doxazosin, terazosin, alfuzosin (potentially confounding agents in included studies: steroids, anticholinergics) | Alpha-blockers improved rates of stone passage: RR 1.45; 95 % CI 1.34–1.57 | NR (data not pooled) | Noted that few studies reported on adverse events |
After excluding studies with potentially confounding drugs other than NSAIDs: RR 1.45; 95 % CI 1.31–1.45 | ||||||
Lu 2012 [26] | 29 | 2,763 | Tamsulosin (potentially confounding agents in included studies: steroids, anticholinergics benzodiazepines) | 19 % improved stone passage rate with tamsulosin | Shorter mean expulsion time by 3.4 days than control group (based on 16 studies) (95 % CI −4.5 to −2.29 days) | Reduced colic (based on eight studies): WMD = 0–0.44 episodes, 95 % CI −0.76 to −0.12) |
Fan 2013 [52] | 20 | 1,593 | Tamsulosin | Lower ureteral stones: P < 0.00001; RR 1.55; 95 % CI 1.43–1.68 | Shorter mean expulsion time by 2.63 days than control group (based on 7 studies): P < 00001,95 % CI −4.13 to −3.12 days) | Reduced colic (based on five studies): P = 0.0003, RR 0.60, 95 % CI 0.45–0.79) |
Did not separate studies using MET as adjunct to SWL | Upper ureteral stones: P = 0.02; RR 1.28; 95 % CI: 1.04–1.57 | Alpha blockers associated with higher risk of side effects (based on eight studies, P = 0.0007; RR 2.17; 95 % CI 1.39–3.40) (most common = dizziness) | ||||
All locations: P < 0.0001; RR 1.51; 95 % CI 1.40–1.63 |
The combined American Urological Association/European Association of Urology Nephrolithiasis Guideline Panel included a discussion of the role of MET in their 2007 Guideline for the Management of Ureteral Calculi [4]. In this document, the panelists summarized a meta-analysis of the six alpha blocker RCTs available at that time by stating that alpha antagonists were associated with a 29 % absolute increase in stone passage rates compared to control, which was statistically significant.
Beyond improving stone passage rates, alpha blockers may also decrease pain associated with ureterolithiasis. Sayed and colleagues randomized 90 patients with distal ureteral stones to either analgesia on-demand with diclofenac or tamsulosin + analgesia [23]. In addition to an absolute increase in stone passage of 38 %, tamsulosin use was associated with a decrease in number of renal colic episodes (1.5 vs 2.5 episodes, p = 0.003) and a decreased use of analgesics (0.14 vs 2.7 vials, p < 0.0001). Porpiglia et al. investigated the role of both tamsulosin and corticosteroids in a 2006 study where they randomized 114 patients to tamsulosin, deflazacort 30 mg daily, both, or analgesia only [24]. While both groups taking tamsulosin experienced significantly higher rates of stone passage, only the group receiving combination therapy with tamsulosin and deflazacort consumed significantly less analgesic than the control group (27 mg vs 81 mg diclofenac, p < 0.001).
Finally, medical expulsive therapy with alpha antagonists may speed stone passage. De Sio and coauthors randomized 96 patients with distal ureteral stones (mean 6.4–6.9 mm) to either diclofenac + aescin (control group) or control therapy + tamsulosin [25] They found the stone passage rate at 2 weeks to be significantly higher in the tamsulosin group (90 % vs. 59 %, p = 0.01) but also noted the alpha blocker was associated with faster stone passage (mean 4.4 vs. 7.5 days, p = 0.005). Other studies have since reported similar findings, summarized by Lu et al. where meta-analysis of 16 studies showed a shorter mean expulsion time with alpha blockers by 3.4 days (95 % CI −4.5 to −2.29 days) [26].
Calcium Channel Blockers
Calcium channel blockers (CCBs) are the most studied medical expulsive agents after alpha blockers. CCBs have been shown to inhibit ureteral contraction and may inhibit spasm without affecting ureteral peristalsis [27, 28]. Drugs in this class that have been studied as MET include nifedipine, diltiazem, and verapamil, though clinical trials have almost exclusively employed nifedipine.
Most of the early studies of nifedipine as MET included combination therapy with an oral steroid agent. For example Borghi and colleagues’ study randomized 86 patients to receive either nifedipine and methylprednisolone or methylprednisolone alone and found a significantly faster and higher stone passage rates in the nifedipine/steroid combination group than steroid alone (87 % vs. 65 %, p = 0.021) [29]. Cooper and colleagues reported similar findings comparing nifedipine and prednisone to analgesia alone (stone passage rates of 86 % vs 54 %, p = 0.001) [30]. The results of similar studies can be found in Table 5.3.
Table 5.3
Published randomized controlled trials of non-alpha blocker medical expulsive agents
Stud year published | Study size | Characteristics of stones | Study arms | Effect on stone passage rates | Effect on time to stone passage | Additional findings |
|---|---|---|---|---|---|---|
Kapoor 1989 [36] | 26 | Ureteral stone (mean 3 mm) | 1. Indomethacin suppository 50 mg 3×/day × 5 days max | No significant difference in stone passage rates | No significant difference in time to stone passage | Indomethacin group had fewer colic episodes, fewer admissions for pain, and significantly lower narcotic use (p < 0.005) |
2. Placebo | ||||||
Borghi 1994 [29] | 86 | Ureteral stone ≤15 mm (mean 6.7 mm) | 1. Methylprednisolone 16 mg/day | Methylprednisolone + nifedipine group had higher stone passage rate (87 % vs. 65 %, p = 0.021) | Faster time to expulsion in Methylprednisolone + nifedipine group (11 vs 16 days, p = 0.036) | |
2. Methylprednisolone 16 mg/day + nifedipine 40 mg/day | ||||||
Cooper 2000 [30] | 70 | Ureteral stone 2–6 mm (mean 3.9 mm) | 1. Nifedipine XL 30 mg/day (max 7 days) + prednisone 20 mg/day (max 5 days) + trimethoprim sulfa | Treatment group associated with a higher stone passage rate than analgesia alone (86 % vs 54 %, p = 0.001) | No difference in time to stone passage | Fewer lost days of work in treatment group (1.8 vs 5.0, p-0.024) |
2. Analgesia | ||||||
Porpiglia 2000 [53] | 96 | Single distal stone ≤10 mm (mean 5.5–5.8 mm) | 1. Deflazacort 30 mg/day (max 10 day) and nifedipine 30 mg/day (max 28 days) | Deflazacort/nifedipine group had higher stone passage rate (79 % vs. 35 %, p < 0.05) | Faster time to expulsion in treatment group (7 vs 20 days, p < 0.05) | Lower consumption of analgesics in treatment group (15 vs. 105 mg of diclofenac, p < 0.05) |
2. Analgesia alone | ||||||
Porpiglia 2004 [54] | 86 | Single distal stone <10 mm (mean 4.7–5.4 mm) | 1. Deflazacort 30 mg/day (max 10 day) and nifedipline 30 mg/day (max 28 days) | Both treatment groups had higher stone passage rate (80 % and 85 % vs 43 %, p < 0.01) | Faster time to expulsion in deflazacort + tamsulosin group than analgesia alone (8 vs 12 days, p = 0.02) | Lower consumption of analgesics in both treatment groups (20 and 26 vs. 105 mg of diclofenac, p < 0.0001) |
2. Deflazacort 30 mg/day (max 10 day) and tamsulosin 0.4 mg/day (max 28 days) | ||||||
3. Analgesia alone | ||||||
Saita 2004 [40] | 50 | Ureteral stone ≤15 mm (mean 12 mm) | 1. Nifedipine slow release 30 mg/day (max 20 day.) and Prednisolone 25 mg/day (max 10 day) | Stone passage 68 % in nifedipine group, 81 % in prednisolone group | NR | |
2. Prednisolone 25 mg/day (max 10 day) | ||||||
Dellabella 2005 [31] | 210 | Single distal stone ≥4 mm (mean 6.2–7.2 mm) | 1. Phloroglucinol 240 mg/day | Tamsulosin associated with higher stone passage rates (97 % vs. 64 % and 77 %, p = 0.001 and <0.0001)
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