Ureteral Stent-Associated Pain: A Review

Abstract

Purpose:

Ureteral stent-related pain is a well-known side effect of stent placement. To date, there is a paucity of resources that address this topic. Herein, we present theories on stent pain pathophysiology, summarize available pain outcome data for different stent designs, and provide an overview of the management of stent pain, including preplacement modifiers, medical management, and other considerations.

Materials and Methods:

This narrative review focused primarily on articles indexed in the PubMed^®, Google Scholar™, and EMBASE databases. No formal search strategy was used and no meta-analysis of data was performed.

Results:

Stent pain pathophysiology is multifactorial and likely a result of mucosal irritation along with retrograde reflux of urine. While there is a consensus on the lack of association between stent length, diameter, and stent-related flank pain, stents should be properly sized so as to prevent dislodgement. Insufficient data exist comparing stent materials and durometry. Multiple drug-eluting stents are in development and have demonstrated promising early results. Alpha-blockers have shown efficacious results and should be considered along with or in combination with anticholinergics and nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of ureteral stent-related symptoms, with judicious consideration of their side effect profiles. Periureteral botulinum toxin A injections are a promising, novel treatment modality.

Conclusions:

Ureteral stent pain is common and multiple modalities have been studied and are in clinical use for its treatment. Care should be taken to avoid placement of stents if possible, with continual reassessment of indications to maintain stents in patients. Relative heterogeneity among studies and small sample sizes make creating specific evidence-based pain management recommendations challenging. Alpha-blockers, antimuscarinics, and NSAIDs are all generally well tolerated and effectively reduce symptoms, but patient-specific factors must be the paramount consideration when choosing monotherapy or combination therapy. Future studies are needed to better define ideal material characteristics and pharmacologic treatments.

Introduction

Ureteral stents are specialized catheters designed to alleviate obstruction by maintaining the patency of the ureteral lumen and to splint the ureter by acting as a scaffold to promote organized tissue healing.¹ Initially conceived as an aid to open surgery on the ureter, ureteral stents evolved to allow for endoscopic placement in 1967, after pioneering work by Zimskind et al.² Naturally, early stent designs were fraught with undesirable complications such as frequent stent migration and expulsion. As a result, ureteral stents were not accepted widely until 1978 after the development of the Double-J and pigtail stents, which sought to minimize stent mobility.^3,4 Since then, significant research has been done to further refine the ideal ureteral stent composition, coating, and design in the hopes of minimizing patient morbidity.

Common issues associated with contemporary ureteral stents include stent-related pain, hematuria, dysuria, urgency, infection, and encrustation. An analysis of 60 patients with unilateral ureteral stents revealed that a majority of patients (80%) reported one or more urinary symptoms.⁵ One study suggested that over 80% of patients experience stent-related pain that affects daily activities, 58% report reduced work capacity, and 32% report sexual dysfunction.⁶ In another series, as many as 32% of patients had ureteral stents removed sooner than anticipated because of these complications.⁷ Clearly, despite advances in stenting technology, patient morbidity remains nontrivial.

Considering the high prevalence among patients and its potential impact on quality of life (QoL) and treatment efficacy, stent-associated pain is a particularly troubling complication of ureteral stenting. The management of ureteral stent pain is complex and depends on a variety of factors. To date, there is a paucity of resources that address this topic holistically. In this review of ureteral stent-associated pain, we seek to present theories on stent pain pathophysiology and summarize available pain outcome data for different stent designs, as well as provide an overview of the management of stent pain, including preplacement modifiers, medical management, and other considerations.

Materials and Methods

We performed a narrative review of relevant research. While no formal search strategy was employed, the following search terms were primarily used to identify relevant sources: ureteral, stent, pain, management, material, alpha blocker, durometry, length, reflux, anti-cholinergic, anti-inflammatory, and drug-eluting. We only considered studies not indexed in PubMed^®, Google Scholar™, or EMBASE and all studies not published in English. Publication date was not considered. References from relevant sources were examined to identify additional sources for this review. A synopsis of relevant references was created.

Ureteral stent-associated pain

Pathophysiology

The exact pathophysiology of stent-related pain remains unknown. Leading theories attribute stent symptoms to the distal end of the stent causing irritation of bladder mucosa, smooth muscle spasm, inflammation, and reflux of urine into the kidneys.¹ Irritative symptoms are observed to be worse during the day, which brings into question the contribution of patient awareness⁵ and stent migration with daytime activity, as some studies have shown that stents move as much as 2.5 cm during daytime activity.⁸ An incomplete distal curl in the bladder⁹ or a stent curl positioned in a renal calix or past the midline of the bladder can increase discomfort.¹⁰ Reflux of urine from the bladder into the kidneys is proposed to be the cause of flank pain, especially with voiding.¹¹ Ureteral stents must allow for a patent connection between the renal pelvis and bladder to allow for decompression, but there is unfortunately no mechanism to prevent retrograde urine flow, especially with high bladder pressures seen in voiding. These theories behind the pathophysiology of ureteral stent discomfort have led to advances in stent design, composition, and coating, and also serve to guide pharmacologic treatment options.

Ureteral stent characteristics and associated symptoms

For years, researchers have been seeking to create the ideal stent that minimizes patient morbidity. Various studies have attempted to characterize the relationship between aspects of stent design and stent-associated discomfort.

Length, positioning, and diameter

After early work suggested that a long intravesical segment contributed to stent discomfort, particular attention has been paid to a possible relationship between stent length and patient discomfort.¹² One study examined 87 patients who received 22, 24, or 26-cm double-pigtail ureteral stents and established that stent length was associated with position of the distal curl (p = 0.02), but was not associated with position of the proximal curl (p = 0.50). They found significant associations between longer stent lengths and urinary frequency (p = 0.04) and urgency (p = 0.02), but did not find a relationship between stent length and flank pain.¹³ Al-Kandari and colleagues¹⁴ echoed these findings when they randomized 120 patients to either correct stent positioning (with the proximal curl positioned in the renal pelvis and the distal curl positioned just beyond the vesicoureteral junction) or longer incorrectly positioned stents (with the proximal curl placed in an upper calix and the distal curl crossing the bladder midline) and found significant differences in dysuria and urgency between the two groups, but no significant difference in flank pain.

However, not all data are consistent on the associations between stent length and patient symptoms. A larger multicenter randomized comparison of stent-related symptoms using the Ureteral Stent Symptom Questionnaire (USSQ) assigned 162 patients to receive either a 6F × 24 cm Contour™ or multilength 6F × 22–30 cm Contour VL™ stent and found a trend to report more urinary symptoms and pain after 4 weeks in the multilength group, but it was not statistically significant.¹⁵ Finally, a recent series of 73 patients found no significant influence of intravesical stent position on associated morbidity, nor did it find a significant association between USSQ subscores for urinary symptoms (p = 0.80), body pain (p = 0.80), general health (p = 0.16), or work performance (p = 0.07) and stent length.¹⁶ Despite these disagreements on associations between urinary symptoms and stent length, there is a general consensus on the lack of association between stent length and stent-related flank pain.

A small number of studies explored how altering the diameter of ureteral stents might affect adverse symptoms. Two groups of researchers compared groups of patients with 4.7F stents against a cohort who had either 6F or 7F stents in place, and both studies showed no significant difference in symptoms.^17,18 Similarly, a prospective randomized trial of 34 patients compared a 4.8F stent with a 6F stent and again saw no statistically significant differences in stent symptom or QoL scores, but the researchers did note a tendency of smaller stents to dislodge more¹⁹ (Table 1).

Table 1.

Stent Length, Positioning, and Diameter: Summary of Selected Outcomes Literature

Reference	Population	Study	Findings
Ho et al.¹³	87 patients who underwent ureteroscopic lithotripsy	Patients were given 22, 24, or 26-cm stents based on operator preference	Stent length was not associated with pain
Al-Kandari et al.¹⁴	120 patients with unilateral stent placement (various indications)	Patients randomized to longer incorrectly placed stents vs correctly positioned stents	Stent position was not associated with pain
Calvert et al.¹⁵	162 patients with urinary tract calculi requiring stent insertion	Patients randomized to 6F × 24 cm Contour™ or multilength 6F × 22–30 cm Contour VL™ stent	Stent length was not associated with pain
Abt et al.¹⁶	73 patients with an indwelling ureteral stent the day before stent removal	Stent position classified into 3 categories by X-ray before stent removal and compared to symptoms	Stent position was not associated with pain
Chandhoke et al.¹⁷	97 patients before extracorporeal shockwave lithotripsy of kidney stones	Patients randomized to three groups: No stent, 4.7F multilength stent, or 7F multilength stent	No difference in pain between 4.7F and 7F groups
Erturk et al.¹⁸	46 consecutive patients undergoing ureteroscopy for stone disease	Patients randomized to either a 4.7F or a 6F stent following the procedure	No difference in pain between 4.7F and 6F groups, 4.7F stents tended to dislodge
Damiano et al.¹⁹	34 patients with unilateral ureteral obstruction due to calculus undergoing stenting	Prospective study of 17 patients with 4.8F and 17 patients with 6F stents	No difference in pain between 4.8F and 6F groups, 4.8F stents tended to dislodge

Material and durometry

Research continues to be done to find the best stent material to minimize patient morbidity, but the results have not been straightforward. Stent durometer values—a measure of the hardness of a material—typically fall between 40 and 90 A, with the transition from soft to hard stents set arbitrarily at 65 A.²⁰ An early prospective study compared four different types of 7F Double-J catheters, including firm Cook polyurethane stents (98 A), Surgitek Silitek Uropass (91 A), Cook C-Flex (90 A), and soft Van-Tec Soft stents (65 A), in 72 patients and found no significant differences among the four types of catheters in terms of frequency, nocturia, flank pain, suprapubic pain, hematuria, and dysuria.²¹ A randomized control trial of 155 patients found significantly higher incidence of dysuria, renal, and suprapubic pain in patients who received the firm polyurethane stent vs a soft Sof-Flex™ stent.²²

A more recent study by Lee and colleagues randomized 44 patients to the Bard Inlay™, Cook Endo-Sof™, Microvasive Contour™, Applied Medical Vertex™, or Surgitek Classic Double-Pigtail™ 6F stents and received responses on the USSQ along with a narcotic diary from 44 patients on days 1, 3, and 5 after stent placement. Other than urinary symptoms being significantly lower in the Inlay™ stent group on day 3 compared with all other groups, there were no significant differences in pain and general symptom scores or narcotic use.²³

Other studies examined novel materials such as segmental metallic stents. A small comparison (n = 41) was done using the USSQ between patients who had conventional Double-J stents and patients who had a new-generation Memokath™ thermoexpandable segmental metallic stent, which revealed a statistically significant reduction in pain, urinary symptom index, and general health in the Memokath cohort.²⁴

Distal loop modifications

Modifications have been made to the distal end of the ureteral stent in the bladder in the hope that less material in situ will result in fewer symptoms. The Tail stent™ (Microvasive/Boston Scientific Corporation) attempted to minimize irritative bladder symptoms with a traditional proximal 7F pigtail that tapered down into a distal lumenless straight 3F tail. In the bladder, the 3F tail did not form a pigtail or coil. The investigators randomized 60 adult patients to receive either a 32-cm 7F Tail stent or a standard 7F double-pigtail Percuflex stent™ (Microvasive/Boston Scientific Corporation). They assessed stent-related symptoms with a scale-based questionnaire at the time of stent removal and 2 weeks after. While the novel design appeared to be associated with significantly few lower urinary tract symptoms, there was no significant decrease in flank or pelvic pain.²⁵

Krebs and colleagues explored a novel buoy stent design (Cook Urological) in a living porcine model that had some similarity to the Tail stent described above. In this design, the proximal end of the stent was a traditional 10F endopyelotomy stent, which tapered distally into a diminutive uncoiled lumenless 3F stent. In the 13 minipigs that survived the study, there was less ureterovesical junction (UVJ) inflammation in the buoy design compared with a 7F control stent, with adequate ureteral flow maintained.²⁶

In a randomized control trial of 236 patients assigned to either control groups, who received either Polaris™ or Percuflex^® stents, or experimental groups that had modified short loop tail stents or long loop tail stents. Short-term comfort outcomes were assessed with the USSQ. Although patients who were stented with short loop tail had less pain medication usage on day 1 and lower pain scores on day 4, the results were not statistically significant²⁷ (Table 2).

Table 2.

Stent Material, Durometry, and Distal Loop Modifications: Summary of Selected Outcomes Literature

Reference	Population	Study	Findings
Pryor et al.²¹	72 patients before placement of 7F double-pigtail catheters	Prospective comparison of symptoms and specific stent durometry values (98, 91, 90, or 65 A)	No significant difference in pain with different stents
Lennon et al.²²	155 patients before placement of double-pigtail stents	Randomized controlled trial of a firm polyurethane stent vs a soft stent	Significant increase in pain in firm stent patients
Lee et al.²³	44 patients before placement of 6F double-pigtail stents	Patients randomized to 5 different brands of stents	No significant difference in pain with different stents
Maan et al.²⁴	41 patients with conventional Double-J stent or a thermoexpandable metallic stent for stricture	Survey about stent-related symptoms (only 41/70 responded) sent to participants	Significant reduction of pain in the thermoexpandable metallic stent group
Dunn et al.²⁵	60 adults before stent placement	Patients randomized to a standard 7F double-pigtail stent vs a 7F Tail stent™ (uncoiled 3F distal end)	No significant decrease in flank or pelvic pain noted
Lingeman et al.²⁷	236 adults requiring retrograde unilateral ureteral stent placement	Subjects randomized in a 1:1:1:1 ratio to the short loop tail stent, the long loop tail stent, the Percuflex Plus stent, and the Polaris stent	No significant difference in pain with different stents

Management of stent pain

Treatment of stent-related pain can be classified into two broad strategies: prevention and management.¹¹ Without a doubt, the most effective way to manage stent-related pain is to prevent placement of a stent initially. This point—although it may seem trite—invites a discussion of judicious use of ureteral stents. It is critically important for urologists to continually reassess indications for keeping a stent in place in patients so as to minimize unnecessary side effects. Once a stent is in place, management strategies of stent-related pain include multiple well-studied pharmacologic options.

Alpha-blockers

Alpha-adrenoreceptor antagonists have been widely utilized for the indications of hypertension and benign prostatic hyperplasia (BPH). Off-label usage of tamsulosin, in particular, has been shown to reduce ureteral stent-related symptoms and improve patient QoL. Tamsulosin is a selective alpha_1A and alpha_1D-adrenoreceptor antagonist, which relaxes the smooth muscle in the prostate, bladder neck, and distal ureter.²⁸ The once daily formulation of tamsulosin provides an optimal pharmacokinetic coverage during a 24-hour period. In addition, it offers an enhanced side effect profile, particularly minimizing hypotension compared with other nonselective alpha-adrenoreceptor antagonists.²⁹

Several possible mechanisms exist in explaining the efficacy of tamsulosin for the treatment of stent-related pain and urinary symptoms. Alpha₁-adrenoreceptors have been found in the human ureter, with the highest density in the distal ureter. Alpha₁-adrenoreceptor antagonists dilate the lumen and reduce spasms by inhibiting basal tone and peristaltic frequency of the ureter.²⁸ Ureteral and local trigonal smooth muscle relaxation, as well as reduced ureteral motility, counteracts the spasms and irritations experienced.³⁰ In addition, Wang et al.³¹ specifically noted a reduction in pain during voiding, suggesting that relaxation of the bladder neck and prostatic smooth muscle consequently led to a reduction in voiding pressure and urinary reflux.³⁰

When considering the choice of alpha-adrenoreceptor antagonist for therapy, it is important to consider the side effect profiles and the impact on the patient's QoL. Kwon and colleagues³² performed a systematic review and network meta-analysis that compared studies utilizing alfuzosin vs tamsulosin vs placebo. The difference in urinary symptom score for alfuzosin vs tamsulosin was not statistically significant as well as the mean difference in body pain score. Overall, the two pharmacologic agents display comparable adverse effect profiles of orthostatic hypotension, dizziness, headache, and fatigue.³⁰

Sexual dysfunction, particularly retrograde ejaculation, is a factor to consider when deciding between these two agents. Rosen and colleagues³³ examined enrolled men in the BPH registry who completed the International Prostate Symptom Score (IPSS), IPSS bother question, five-item International Index of Erectile Function (IIEF-5), and the three ejaculatory function items of the Male Sexual Health Questionnaire (MSHQ-EjD). Overall, the IIEF-5 and MSHQ-EjD short-form scores were higher, suggesting better erectile and ejaculation function for men taking the alpha_1A subtype nonsuperselective alpha-blockers such as alfuzosin than those taking the alpha_1A-subtype superselective tamsulosin.³³ Hellstrom and Sikka³⁴ compared the effects of tamsulosin 0.8 mg daily vs alfuzosin 10 mg daily on ejaculation in healthy adult men. The results showed a statistically significant decreased ejaculate volume in the tamsulosin vs alfuzosin study arm (Table 3).

Table 3.

Alpha-Blockers: Summary of Selected Outcomes Literature

Reference	Population	Study	Findings
Wang et al.²⁹	154 patients who underwent insertion of a Double-J ureteral stent after ureteroscopic stone removal	Patients were given tamsulosin 0.4 mg once daily vs placebo for 2 weeks	Significant improvement in body pain with tamsulosin
Kwon et al.³²	Meta-analysis with seven RCTs (n = 696)	Systematic review and network meta-analysis for alfuzosin vs tamsulosin vs placebo	Significant improvement in body pain with alpha-blockers

Anticholinergic agents

Anticholinergic agents antagonize muscarinic receptors and exert their effects through modification of urinary bladder contraction. FDA indications for these agents include the treatment of overactive bladder: urgency, frequency, and urge incontinence. Several agents have been utilized as monotherapy or in combination therapy with alpha-blockers for the management of stent-related symptoms. Currently, there is conflicting evidence with the use of anticholinergics as to whether there is an actual benefit of relieving stent-related symptoms or if a synergistic effect exists by employing a combination-based pharmacotherapy regimen with alpha-blockers. Solifenacin and tolterodine (extended release and immediate release) both act as competitive cholinergic receptor antagonists and offer a once daily dosing regimen. Oxybutynin exhibits a direct antispasmodic effect on smooth muscle and also inhibits the action of acetylcholine on smooth muscle. Oxybutynin also offers an extended-release formulation with a once daily dosing regimen.³⁵

Possible explanations for the efficacy of anticholinergic agents in the management of stent-related symptoms include the muscarinic receptor specificity at the detrusor muscle. In addition, the stent itself may unmask or exacerbate preexisting subclinical detrusor overactivity causing involuntary bladder contractions, thus setting the rationale for using anticholinergic agents.³⁶ Lee and colleagues³⁷ evaluated the efficacy of solifenacin monotherapy 2 weeks after operation with the USSQ (Chinese version)—a modified questionnaire consisting of urinary symptom score and body pain score and elements of the IPSS as an objective measure of stent-related symptoms. Solifenacin vs control showed statistically significant benefits in lower urinary tract symptoms, stent-related pain, and hematuria in both genders. It is postulated that solifenacin relieves irritation, body pain, and hematuria by alleviating bladder, ureteral spasm, and retrograde pressure transmission to the kidney.³⁷ Comparing tamsulosin and solifenacin in a head-to-head randomized controlled trial, EL-Nahas and colleagues³⁸ concluded that solifenacin outperformed tamsulosin in relieving stent-related symptoms with a statistically significant lower total USSQ score in all domains except sexual index. Although in this study solifenacin proved to be superior, it cannot be ignored that tamsulosin has established effectiveness and that we should strive to create patient-specific pharmacotherapy regimens.

Several studies have looked at the effectiveness of combination therapy consisting of tamsulosin and solifenacin. Lim et al.³⁹ assessed patients at 1 day postoperatively with the IPSS/QoL and visual analog pain scale (VAPS) questionnaires and reported statistically significant benefits with combination therapy in total IPSS compared with the tamsulosin/solifenacin only group. However, there are several factors to consider, including the tamsulosin dose of 0.2 mg daily, which is the standard dose approved for Korean patients, and the absence of stent-specific questionnaires such as the USSQ. Conflicting evidence shown by Park and colleagues⁴⁰ showed that tamsulosin/solifenacin monotherapy and combination therapy provided no benefit in relieving stent-related symptoms. Patients were assessed with USSQ at week 2, the day of stent removal, and at week 6, the patient's return to baseline QoL. USSQ results, which were stratified by medication regimen at both assessment points, did not show statistically significant efficacy outcomes.

Another anticholinergic agent, tolterodine (immediate release and extended release), has been used in combination with alpha-blockers: alfuzosin and terazosin. Park and colleagues⁴¹ examined alfuzosin and tolterodine extended release as monotherapy with the USSQ administered at 6 weeks after stent placement to assess stent-related symptom improvement. This study concluded that there was no significant difference in the six domains of the USSQ between alfuzosin and tolterodine extended release. Both alfuzosin and tolterodine extended release showed statistically significant improvements in urinary symptom score and body pain score. Tehranchi and colleagues⁴² found that combination therapy of terazosin and tolterodine immediate release resulted in significant reductions in total IPSS, irritative symptoms, QoL, flank pain, voiding pain, and decreased analgesic use compared with placebo. One caveat is that randomization resulted in more patients who underwent percutaneous nephrolithotomy in the combined therapy group; therefore, this can explain a significant improvement in flank pain.

Sivalingam and colleagues⁴³ performed a double-blinded, randomized controlled trial examining the efficacy of combination therapy: tamsulosin 0.4 mg and tolterodine ER 4 mg compared with tamsulosin 0.4 mg monotherapy. The USSQ was administered before stent placement on the day of surgery, the day after stent placement, the morning of stent removal, and the day after stent removal. Combination therapy did not show a significant difference in urinary symptoms, body pain, and activities of daily living from baseline to just before stent removal. Of note, general health index and sexual matters USSQ score changes from morning after stent placement and 7 days after stent insertion/morning of stent removal were statistically significant. Combination therapy provided a score change of −0.49 vs 0.05 for monotherapy (p = 0.0271). Sexual matters score showed a significantly worse score change in the combination therapy group vs monotherapy. (0.219 vs −0.063; p = 0.0108) However, Sivalingam and colleagues discuss several key points of possible confounding and critique of their study. There was no observed urinary retention in any patient on tolterodine ER; however, the authors state that the side effect profile of tolterodine ER may have offset some of its perceived benefits on irritative bladder symptoms. In addition, the study may not have permitted tolterodine ER to reach its optimal therapeutic window.⁴³

Oxybutynin extended release, an antispasmodic agent was trialed in Norris et al.,⁴⁴ yielding no significant difference in flank pain, suprapubic pain, urinary urgency, urinary frequency, and dysuria. The symptom questionnaire and VAPS was administered on postoperative days 1 and 2, which may have been too premature for the full pharmacodynamic response of the medication regimen to take effect. The authors concluded that their study was inconclusive and that a future study with a larger sample size may show statistical significance.

Cholinergic/muscarinic receptor antagonists have a constellation of adverse effects that can exacerbate urinary symptoms and paradoxically decrease QoL. Among the possible adverse effects are dementia, blurred vision, headache, dry mouth, orthostatic hypotension, ileus, and urinary retention. Most of the studies discussed in this section reported minimal side effects and stated that regimens were well tolerated. Zhou and colleagues⁴⁵ performed a meta-analysis of studies involving alpha-blockers, antimuscarinics, or combination therapy for relieving ureteral stent-related symptoms and discussed adverse events experienced in studies in its Safety section. Tehranchi and colleagues⁴² reported that 3 patients in the antimuscarinic group experienced orthostatic hypotension and dry mouth, as well as 11 patients in the combination therapy group who had orthostatic hypotension, headache, and dry mouth.

The American Geriatrics Society 2015 Updated Beers Criteria Update Expert Panel⁴⁶ performed a comprehensive systematic review on drug-related problems and adverse drug events in older adults. Table 7 in Ref.⁴⁶ highlights several antimuscarinic agents used for ureteral stent-related symptom relief: oxybutynin, solifenacin, and tolterodine—Drugs with Strong Anticholinergic Properties. Although agents such as oxybutynin are intended to be used for short-term treatment regimens, it has been implicated in drug-induced cognitive impairment in older patients >65 years of age. Katz et al.⁴⁷ utilized interviewer and computer-administered tests to evaluate cognitive function after oxybutynin administration. The ability of oxybutynin to cross the blood–brain barrier is a possible mechanism for affecting memory and cognitive functions. Oxybutynin caused significant cognitive decrements on several cognitive measures, indicating that alternative treatment regimens should be considered when elderly patients undergo ureteral stent placement procedures. Overall, anticholinergic agents have shown efficacious results and should be considered along with alpha-blockers in the treatment of ureteral stent-related symptoms with judicious assessment of patient-specific factors to avoid potential adverse events (Table 4).

Table 4.

Anticholinergic Agents: Summary of Selected Outcomes Literature

Reference	Population	Study	Findings
Lee et al.³⁷	70 patients who received Double-J stent after lithotripsy	Patients given solifenacin 10 mg once daily vs age/sex-matched patients without solifenacin therapy	Solifenacin group had significantly less flank, abdominal, and urethral pain scores (all p < 0.05)
El-Nahas et al.³⁸	131 patients who received unilateral stent for calculus or after lithotripsy	Patients given tamsulosin 0.4 mg once daily vs solifenacin 5 mg once daily vs placebo until stent removal	Tamsulosin and solifenacin group showed statistically significant decrease in pain index p < 0.001
Lim et al.³⁹	168 patients who underwent Double-J stent insertion after ureteroscopy for calculus	Patients given solifenacin 5 mg once daily vs tamsulosin 0.2 mg once daily vs combination therapy vs no medication	VAPS—no significant findings. IPSS—significant decrease in irritative subscore on day of stent removal in solifenacin only and combined groups
Park et al.⁴⁰	131 patients who received stent for calculus or after ureteroscopic lithotripsy	Patients given solifenacin 5 mg once daily vs tamsulosin 0.2 mg once daily vs combination therapy vs control	Comparison of the six USSQ domain scores at week 2 showed no differences.
Park et al.⁴¹	52 patients who received Double-J stent after urological surgery	Patients given alfuzosin 10 mg once daily vs tolterodine ER 4 mg once daily vs placebo for 6 weeks	No significant differences in the body pain scores
Tehranchi et al.⁴²	104 patients who received a stent after lithotripsy or percutaneous nephrolithotomy	Patients given terazosin 2 mg twice daily vs tolterodine 2 mg once daily vs combination therapy vs placebo	Patients receiving terazosin plus tolterodine experienced significant reductions in flank pain and voiding pain
Sivalingam et al.⁴³	80 patients who received double-pigtail stents after ureteroscopy	Patients given tamsulosin 0.4 mg and tolterodine early release 4 mg vs tamsulosin 0.4 mg and placebo	No significant difference in body pain from baseline to just before stent removal
Norris et al.⁴⁴	60 patients who received unilateral stent after ureteroscopy	Patients given blister pack containing 21 unmarked capsules of extended release oxybutynin 10 mg, phenazopyridine 200 mg, or placebo	No difference in bothersome score among the groups for pain
Zhou et al.⁴⁵	Meta-analysis of 13 articles (n = 1408)	Randomized controlled trials evaluating effects of alpha-blockers, antimuscarinics, and combination therapy for stent-related symptoms	Alpha-blocker group showed statistically significant decreased body pain index score, combination therapy group showed statistically significant difference in VAPS

IPSS = international prostate symptom score; USSQ = ureteral stent symptom questionnaire; VAPS = visual analog pain scale.

Oral nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) provide an effective opioid-sparing pain regimen, especially in the setting of ureteral stent-related pain management. Chaignat and colleagues⁴⁸ discuss the expression of both cyclooxygenase (COX)-1 and COX-2 receptors in human ureters detected by immunohistochemistry. The receptors were localized to the urothelium, smooth muscle cells in the tunica muscularis of ureters, and to the tunica media of blood vessels. The presence of COX-1 and COX-2 receptors in human ureters provides another target for pharmacological intervention to manage ureteral stent-related pain.

Tadros and colleagues⁴⁹ discuss the utilization of a single NSAID dose before ureteral stent removal in preventing severe pain after ureteral stent removal was assessed. The authors explain several mechanisms of NSAIDs reducing ureteral contractility and renal blood flow by inhibiting renal prostaglandin synthesis. This in turn decreases the pressure in the renal pelvis and ureter. A prospective, randomized, double-blinded placebo-controlled trial was performed with the administration of rofecoxib 50 mg or placebo before ureteral stent removal. NSAIDs were given to patients no less than 15 minutes before stent removal and a VAPS was administered. Among the NSAID group, zero of 10 reported severe pain (VAPS score of >7). In addition, the narcotic requirements decreased from 8.19 mg morphine equivalents in those patients with severe pain to 1.67 mg in the NSAID group. Perhaps future studies need to further investigate the potential to take prophylactic measures in pain management with NSAIDs, alpha-blockers, and anticholinergics.

Drug-eluting stents

The principles of pharmacodynamics not only emphasize the drug–receptor mechanism but also simply the delivery of drug in an effective concentration to the desired site of action. In this section, we will discuss the utility of drug-eluting ureteral stents in the setting of ureteral stent pain control. Drug-eluting stents attempt to address the challenge of delivering medication to the ureteral tissue directly. Drug delivery through self-expandable stents similar to those used in cardiology might be more effective as they expand to act as a mechanical scaffold, enabling drug release in close proximity to ureteral tissue.⁵⁰

Intraluminal hyperplasia represents one of the most common causes of ureteral stent obstruction. This mechanism of hyperplasia frequently compromises vascular stent patency.⁵¹ Liatsikos et al.⁵² and Kallidonis et al.⁵¹ evaluated the effectiveness of drug-eluting stents in minimizing neointimal hyperplasia and maintaining the patency of stents in animal models. In the Liatsikos et al. study,⁵² the paclitaxel-eluting coronary stent (Boston Scientific) was used in female pig ureters, resulting in less inflammation and hyperplasia compared with bare metal stents. Subjects were examined at a 21-day follow-up where degree of hyperplasia and stent patency was assessed. Paclitaxel is an oncologic agent with a powerful antiproliferative effect that promotes microtubule assembly by enhancing the action of tubulin dimers and inhibiting disassembly of microtubules. This action interferes with cell replication, thus causing cell death.⁵² Kallidonis and colleagues⁵¹ utilized the zotarolimus-eluting stent in porcine and rabbit ureters to evaluate the effect on reducing hyperplastic reaction. Although the hyperplastic reaction was present in all cases, CT urography results revealed significantly more hyperplasia in bare metal stents. Zotarolimus is an immunosuppressant derivative of rapamycin used with phosphorylcholine as a carrier displaying an antiproliferative effect to inhibit hyperplasia.

Biofilm formation and encrustation of ureteral stents can activate the inflammatory pathways precipitating ureteral stent-related pain. Mendez-Probst and colleagues⁵³ investigated the anti-inflammatory effects of the antimicrobial agent, triclosan. The Triumph^® triclosan-eluting stent showed statistically significant reductions in lower flank pain scores during activity, urination, abdominal pain during activity, and urethral pain during urination. Subjects completed an analog-scale symptom assessment questionnaire, not the validated USSQ.

Barros and colleagues⁵⁴ investigated impregnation of ketoprofen by CO₂ impregnation in biodegradable ureteral stents. Ketoprofen is a nonsteroidal anti-inflammatory agent that reversibly inhibits COX-1 and -2 enzymes, thus reducing the formation of prostaglandin precursors. This in vitro study examined the impregnation of ketoprofen in biodegradable ureteral stents at different temperatures. The elution profile in vitro displayed promising kinetics data in the first 72 hours, the necessary time for anti-inflammatory delivery after the surgical procedure.⁵⁴ Supercritical fluid technology using carbon dioxide for processing pharmaceutical active compounds allows delivery of the active agent into polymer matrices. Several chemical advantages exist with this method of drug delivery: high diffusivity, low surface tension, and ease to separate/recover solvent of carbon dioxide. The ideal temperature for optimal impregnation yield of ketoprofen was found to be at 40°C. This novel concept is promising as we have direct action of the anti-inflammatory agent through a biodegradable ureteral stent; however, further studies with human subjects must be evaluated for safety and efficacy for ureteral stent pain management.

Piggybacking on the concept of local anti-inflammatory agent delivery, Krambeck et al.⁵⁵ performed a multicenter, prospective randomized trial investigating the safety and efficacy of a ketorolac-loaded ureteral stent in symptom management. Ketorolac is analogous to ketoprofen in mechanism of action as reversible inhibitor of COX-1 and -2. It has been shown to decrease renal perfusion pressure and ureteral smooth muscle contractility in animal models of ureteral obstruction.⁵⁶ Patients were randomized to ketorolac-loaded or control stents after ureteroscopy. The primary endpoint was an intervention for pain defined as unscheduled physician contact, change in pain medication, or early stent removal. A limitation of the study was not using the USSQ. Safety of the ketorolac-loaded stent was established by the fact that adverse events were not statistically different from control stents. The authors report a statistically significant lower mean pain pill count at day 3 in the ketorolac-loaded stent group.⁵⁵ The biggest obstacle to drug-eluting stents is the nature of the urothelium, which may provide too great a barrier for effective drug delivery.⁵⁷ The urothelium is a type of transitional epithelium consisting of multiple layers of epithelial cells connected by tight junctions. The challenge for future drug-eluting stents lies in the delicate balance between effective drug delivery through the urothelium and adverse events caused by compromising the protective urothelial barrier (Table 5).

Table 5.

Oral Nonsteroidal Anti-inflammatory Drugs, and Drug-Eluting Stents: Summary of Selected Outcomes Literature

Reference	Population	Study	Findings
Tadros et al.⁴⁹	22 adults with an indwelling ureteral stent after ureteroscopy	Patients randomized to receive either a single dose of placebo or an NSAID (rofecoxib 50 mg) before ureteral stent removal	Complete prevention of severe pain with NSAID after ureteral stent removal
Mendez-Probst et al.⁵³	20 adults requiring short-term stenting	Patients randomized to receive either a Percuflex Plus^® noneluting stent+levofloxacin prophylaxis (control) or a Triumph^® triclosan-eluting stent	Significant reductions in lower flank pain in the Triumph cohort
Krambeck et al.⁵⁵	276 patients undergoing ureteroscopy for diagnosis or stone removal	Patients were randomized 1:1 to ketorolac-loaded or control stents	Significant reduction in mean pain pill usage in the ketorolac group on day 3 after stenting

NSAIDs = nonsteroidal anti-inflammatory drugs.

Botulinum toxin type A

Recently, there has been interest in using periureteral botulinum toxin type A injection—a potent inhibitor of presynaptic acetylcholine release—to control stent pain. A prospective single-blind study randomized 51 patients to botulinum toxin type A injection (10 U/mL at three periureteral locations) or control (no injection) after unilateral stent insertion. Patients completed the USSQ on postoperative day 7 and the reported postoperative pain score between the botulinum toxin type A and control group was significantly lower (3.4 vs 6.0; p = 0.02).⁵⁸ More research is required to better evaluate botulinum toxin as a novel treatment strategy.

Conclusion

Urologists commonly employ ureteral stents, and ureteral stent pain is a well-known side effect of stent placement. Care should be taken to prevent placement of stents if possible, with continual reassessment of indications to maintain stents in patients. In patients with stent pain, multiple modalities of pain control were discussed in this review consisting of different stent designs, pharmacologic agents, and novel drug delivery technologies. It is evident that the gold standard for ureteral stent-related pain management is elusive and perhaps does not even exist.

Heterogeneity among studies and relatively small sample sizes limit the ability to create specific evidence-based pain management recommendations. Standardizing outcomes measurement methodology would allow for more appropriate comparison of different pain-modifying modalities. More knowledge must be ascertained as to the exact mechanism of injury or inciting factors for ureteral stent-related pain to better target therapeutic options for patients. Careful analysis of the patient's indication for ureteral stent, urological history, and risk factors must be assessed. The stent should be properly sized to prevent dislodgement. Based on the current theories of ureteral stent-related pain, it is clear that a multifactorial mechanism of pain may require synergistic treatment modalities with different mechanisms of action. Patient-specific factors must be the paramount consideration when choosing the optimal pain management regimen. Future studies are needed to better define ideal material characteristics and pharmacologic treatment synergism.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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