Keywords

1 Introduction

Double ‘J’ (DJ) ureteral stenting is amongst the commonest procedures performed in urology as an adjunct since its first inception in 1978 by Finney [1]. However, there are complications (SRS) such as infection, and encrustation associated with its use, together with uncomfortable lower urinary tract symptoms (LUTS). The latter are known as stent related symptoms (SRS) and are commonly reported in the literature. SRS mentioned in literature are urgency, frequency, dysuria, haematuria, pain in the suprapubic and flank region. These can result in decreased sexual activity, reduced work performance, as well as decreased quality of life (QoL) in more than two-third of the patients [2]. Advancements have been made in stent design in order to try to reduce the irritation and discomfort using different biomaterials and coatings. Despite this, drugs still hold the key in reducing the morbidity related to the ureteral stents. In this chapter we attempt to throw light on the pharmacotherapy used to reduce ureteral stent related morbidity.

2 Reasons for Stent Related Symptoms (SRS)

Discomfort caused by the ureteral stents is one of the most common problems associated with DJ stenting. In order to better identify the gravity of the problem and quantify the level of discomfort, Ureteral Stent Symptom Questionnaire (USSQ) was developed and validated by Joshi et al. [2]. USSQ paved the way for multiple studies that tried to identify the cause of stent related discomfort. One study from Al-Kandari et al., reported that the distal end of stent crossing midline was one of the major causes of stent related discomfort [3]. Another randomised control trial (RCT) by Chew et al., showed that excess length of stent in the bladder caused severe urgency and dysuria in patients [4]. As described by Ramsay and Venkatesh et al., stent related reflux of urine during micturition was reported to cause ipsilateral renal pain [5, 6]. Also movement of stent occurs has been described during daily routine activities and it moves up to 2 cm in both in kidney and bladder sides, adding to irritation and inflammation of the urothelium [7, 8]. Significant progresses have been made in stent design keeping these factors in mind, to reduce the irritation and discomfort using suitable biomaterials to improve the biocompatibility, however the stent’s movement is unavoidable. One of the intriguing effects of stent placement is the activation of “hyperperistalsis” during which the ureter contracts trying to expel the stent. This mechanism continues until the ureteric peristaltic activity stops and reaches a state of “aperistalsis” [9, 10]. This was proposed as one of the theories to understand the cause of ipsilateral pain and hydronephrosis and was explained by Rajpathy et al. as a consequence of the slow drainage of urine from the kidneys caused by the aperistalsis. Many authors have shown that selective alpha blockers such as Tamsulosin and Alfuzosin, have the effect of decreasing stent related pain and discomfort by reducing the peak ureteral contraction pressure and the global contractility [11,12,13,14,15,16,17]. The mechanisms of action of these drugs that have the effect of minimising SRS, is still under study. Several studies have suggested that both these mechanisms may be possible, either decreasing the peristalsis or relaxing the hyperperistaltic obstructed segment of ureter thereby restoring normal peristaltic movement. The latter mechanism if true, may also reduce the hydronephrosis caused by the aperistalsis after stent insertion [11,12,13,14,15,16,17].

2.1 Role of Alpha-1 Blockers/Antagonists

The alpha-adrenoreceptors, when activates, result in the contraction of the smooth muscles. They are present in the distal ureteric mucosa, trigone of bladder and in the prostatic urethra. The ureteral stents cause stimulation of these regions which lead to irritation, contraction and spasms, thereby causing LUTS. Pain in the flank region caused by urinary reflux through the stents has also been documented [13, 18,19,20,21]. The earliest mention of alpha-1 blockers for the treatment of (LUTS) was reported in 1900 by Michel et al. [22]. Alpha-blocker inhibits the above mentioned contraction and thereby relaxes the smooth muscles which in turn prevents spasms and decreases the resistance of bladder outlet. This mechanism also reduces intra-vesical pressure during voiding which indirectly decreases the urinary reflux to the kidneys [23, 24].

2.1.1 Silodosin

Silodosin is a highly selective alpha-1a blocker with 160 and 55 times affinity towards alpha-1a subtype and 1b and 1d receptors respectively. In 1995, it was initially introduced as KMD-3213 and since then its role in medical management of Benign Prostatic Enlargement (BPE) has been established [24,25,26,27]. Silodosin has high affinity towards the alpha-1a receptor subtype, which are densely located in the smooth muscles of lower urinary tract. Owing to this highly selective action, it has lower adverse cardiovascular effects such as postural or orthostatic hypotension [24]. This implies that Silodosin has higher safety index than other alpha-1 blockers for patients with SRS especially those affected by cardiovascular disease, frailty, postural instability and low blood pressure.

2.1.2 Tamsulosin

Tamsulosin is a selective alpha 1a and 1d-adrenoreceptor blocker [28]. The dosage is once daily and causes less postural/orthostatic hypotension as compared to other non-selective drugs of the same class [29]. The mechanism of action in relieving SRS has been described by Lamb et al. and it is similar to the other drugs of the same category [30].

2.1.3 Alfuzosin

Also Alfuzosin effectively inhibits Alpha-1 adrenoreceptor-mediated contraction of bladder, prostate and proximal urethral smooth muscle with a favourable side effect profile [31,32,33,34,35,36]. Alfuzosin also has once-a-day dosage which has resulted in better patient compliance [33]. The two most commonly reported side effects are headache and dizziness. However their intensity is mild and does not require alteration of dosage or stoppage of medication [34].

2.1.4 Naftopidil

Naftopidil is found to have very high affinity towards alpha 1D subtype of adrenergic receptors as compared to others (3 times higher than alpha 1a; 17 times higher than alpha 1b) [36]. Hence, theoretically naftopidil may be more beneficial in treating SRS [37]. However not enough literature is available regarding their use in alleviating SRS.

2.2 Role of Antimuscarinics/Anticholinergics

2.2.1 Solifenacin and Tolterodine

Detrusor muscle incorporates a high density of muscarinic receptors. Tolterodine and Solifenacin are competitive antagonists of the muscarinic receptors, thereby; they modify the contractility of the detrusor muscle. They are available in immediate, modified or extended release formulations. Firstly, as SRS may be due to the detrusor overactivity (OAB/DOA) caused by the bladder wall irritation, these are inhibited by antimuscarinics. Secondly, subclinical OAB/DOA may be highlighted by SRS and can also be managed by this group of drugs [38, 39]. Adverse effects associated with antimuscarinics are headache, blurred vision, orthostatic hypotension, dry mouth, constipation, and urinary retention [38, 39]. This can influence the patient’s quality of life and reduce the compliance to the medication.

2.3 Post Ganglionic Blockers

2.3.1 Oxybutynin

Oxybutynin has anti-cholinergic action at the post ganglion level of the smooth muscles, thereby providing an antispasmodic effect. Similarly to Solifenacin and Tolterodine, Oxybutynin is also available in immediate and extended release formulations [40]. One major drawback of its extended use is that, Oxybutynin can cross the blood-brain barrier and cause cognitive impairment in patients >65 years of age [40].

2.3.2 Trospium Chloride

Trospium chloride has a parasympatholytic effect by opposing the action of acetylcholine on muscarinic receptors in bladder. It therefore relaxes the bladder smooth muscle. This has proved to be effective in relieving SRS related to bladder muscle spasms due irritation by the stent [41]. This drug is also better tolerated in older age groups due to fewer incidences of central nervous system (CNS) adverse reactions thanks to its reduced ability to cross the blood-brain barrier.

2.4 Beta-3 Agonists

2.4.1 Mirabegron

The role of Mirabegron is already established in overactive bladder by reducing the detrusor overactivity. Hence, it was postulated to also be able to reduce the overactivity caused by the ureteral stent in the bladder, thereby decreasing SRS. Mirabegron belongs to the family of Beta-3 agonist’s drugs and its mechanism of actions seems reducing SRS similarly to antimuscarinics. In view to its reduced side effects, its role in SRS treatment is currently being reconsidered [42,43,44].

2.5 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Cyclooxygenase receptors are present in tunica muscularis of urothelium, ureters as well as in tunica media of blood vessels. By targeting these receptors in the ureters, NSAIDs can contribute to manage stent related pain. They inhibit the prostaglandin synthesis causing ureteral relaxation which indirectly decreases intrarenal and intraureteral pressure [45, 46]. Thus their use in alleviating stent related pain and discomfort is justified.

2.6 Phosphodiesterase 5-Inhibitors (PDE5I)

2.6.1 Tadalafil

Smooth muscle relaxation is mediated by an intracellular increase of cAMP and cGMP. The role of PDE5-I is already established in medical expulsion therapy (MET) for ureteral stones and decreasing LUTS in benign enlargement of prostate [47,48,49]. This led to the idea of their usage in alleviating stent related symptoms. Although the studies are in a preliminary stage, the results have suggested PDE5I to be a better option in patients with sexual dysfunction related to ureteral stents [49].

3 Miscellaneous

3.1 Botulinum Toxin

Botulinum toxin type A (BotoxA) injection has an established role in management of overactive bladder (OAB) based on its mechanism of inhibition of presynaptic acetylcholine release. Based on this, it was hypothesized that stent related discomfort caused by overactivity due to ureteral irritation could be managed by the same mechanism. Gupta et al. administered Periureteral BotoxA injection (10 U/mL) at three locations. The results suggested that after these injections, the analgesic requirement reduced significantly. Their role is still experimental as the exact pain-relieving mechanism is not known. It is postulated that this works inhibiting the release of various neuromodulators such as substance P, calcitonin gene-related protein (CGRP) as well as glutamate. The associated risks mentioned are urinary retention due to muscle paralysis, bleeding from the periureteral injection sites and vesicoureteral reflux [50,51,52,53].

3.2 Pregabalin

Pregabalin is a gamma-aminobutyric acid (GABA) agent and it has been FDA approved for neuropathic pain, central pain and chronic pain. Recent interest has developed in the use of this drug to treat LUTS [54, 55]. Pregabalin works by reducing the neuronal excitability by decreasing the synaptic neurotransmitter release which in turn inhibits afferent C nerve fiber evoked responses for inflammation [55]. It also centrally inhibits the dorsal horn neuron which results in reduced sensation of pain caused by inflammation. Despite there is no clear evidence in the literature supporting the use of pregabalin in reducing SRS, few authors have hypothesized it can play this role based on its combined peripheral and central mechanisms of action [55].

3.3 Calcium Channel Blockers (CCB)

There is no strong evidence to support the role of CCB in relief of stent related symptoms. Recently, Lee et al. hypothesized that ureteral relaxation can be improved with local administration of vasodilators such as CCB [56]. The authors found that CCB (nifedipine) significantly relaxed the human ureteral smooth muscle cells with reduced ureteral contraction amplitude and frequency by 90% and 50%, respectively [56]. Hence, their use in conditions such as ureteric calculus and stent related symptoms cannot be ignored.

4 Evidence Regarding Combination Therapy

4.1 Alpha-Blocker and Anti-muscarinics/Anticholinergics Combination

Various studies including more than 700 patients, have described the role of combination therapy to be better than placebo across all domains of USSQ such as general health, urinary symptoms, work performance, sexual health and pain score as well as significantly decreased IPPS and QoL scores [55, 57,58,59,60,61,62].

Studies have been carried out comparing combination therapy versus monotherapy.

Alpha blockers monotherapy have been compared with combination therapy and antimuscarinics single treatment with combination therapy. The comparative studies [55, 57,58,59,60,61,62] included more than 500 and 700 patients respectively. The analysis clearly showed greater benefit with combination therapy in terms of USSQ domain scores, reduction of International prostate symptom score (IPSS) and improvement in QoL score. The values across all domains were statistically significant in favour of combination therapy as compared to either monotherapy [55, 57,58,59,60,61,62].

5 Complementary and Alternative Medications (CAM)

CAM is aimed to prevent or treat a condition but is not considered a part of the conventional medicine approach [63]. There are no published reports or evidences directly pointing to the benefits of alternative plant based or herbal medications in preventing ureteral stent related symptoms. However the results from few reports indicate their effect in reducing bladder over activity.

5.1 Chinese Herbal Medicines

Chinese herbal medications namely Hachi-mi-jio-gan and Gosha-jinki-gan contain multiple herbs which activate the spinal kappa opioid receptors and cause reduction in the bladder sensation and contractility. Their benefits on IPSS, overactive bladder symptom score (OABSS) and QoL scores have been demonstrated in various studies [64,65,66,67].

5.2 Capsaicin

Capsaicin belongs to the genus Capsicum. It has a similar action to the previously mentioned Chinese herbs desensitizing C-afferent neurons and thereby decreasing bladder contractility and sensations. However, no many human studies have been performed using this ingredient to date [68].

5.3 Pumpkin Seed Extract

Pumpkin seed oil extracts have been used to treat LUTS. Several studies have demonstrated their beneficial effects in reducing storage symptoms and improving OAB symptoms [67,68,69].

5.4 Homeopathic Options

Natrum miraticum, causticum, sepia, paeira, zincum and pulsatilla are some of the homeopathic medications used to treat LUTS such as increased urinary frequency or urinary retention due to bladder paralysis especially in the post- operative period [70, 71]. There have not been any human clinical trials assessing the efficacy of these medications with ureteric stents.

6 Conclusions

In terms of monotherapy, Alpha blockers as well as Antimuscarinics are effective in reducing SRS. Role of Mirabegron in the field is currently gaining importance. However, combination therapy reaches better outcomes than monotherapy alone while in cases with sexual dysfunction along with stent related symptoms, PDE5-I are better than other options. The role of complementary therapy for SRS with natural remedies is promising but needs to be assessed further. More randomised studies and laboratory trials are necessary to analyse possible alternative treatments for SRS that can heavily affects patients’ quality of life.