Intravesical indwelling lidocaine‑releasing devices for IC/BPS (Review)

. Since the time the first case of interstitial cystitis/bladder pain syndrome (IC/BPS) was reported, there have been complaints of a decreased quality of life secondary to bladder pain; thus, effective treatment(s) are required. Several treatments have been developed, among which the intravesical instillation of lidocaine is considered one of the most favorable treatments due to the rapid local anesthetic action with minimal systemic side‑effects, and even serves as a potential diagnostic tool for IC/BPS. In addition, the anti‑inflammatory effects of lidocaine are associated with a longer duration of pain relief as compared to the effects of local anesthetic by breaking the vicious cycle of neurogenic inflammation. However, the main difficulty encountered with this treatment is the low absorption rate and the lack of maintaining a monthly effect. To overcome this difficulty, several approaches, including alkalization or the use of drug cocktails have been attempted. Recently, several indwelling lidocaine‑releasing devices have been developed; however, the majority of these devices have not yet entered clinical trials, at least to the best of our knowledge. The only device evaluated in phase II clinical trials to date has failed to demonstrate a statistically significant efficacy compared to the placebo group. If the efficacy is improved and further clinical evidence is collected, the use of IC/BPS as a treatment strategy may become feasible.


Introduction
The effective treatment of interstitial cystitis (IC)/bladder pain syndrome (BPS) is mandatory due to severe bladder pain, pressure and discomfort, which in turn negatively affects the quality of life (QoL) of patients (1). Intravesical instillation is considered a promising treatment strategy as intravesical instillation delivers drugs directly and locally to the bladder mucosa; a number of drugs have been tested using this treatment technique (2)(3)(4). Specifically, lidocaine has achieved a documented level of success in relieving the symptoms of IC/BPS, and also has the potential to serve as a diagnostic tool for IC/BPS. The main difficulty encountered with the intravesical instillation of lidocaine is the limited duration of the local anesthetic activity; however, several devices have been developed to overcome this issue. The present review article summarizes the mechanisms underlying the intravesical instillation of lidocaine, the current therapeutic and diagnostic evidence, and also provides a comprehensive summary of the published clinical experience to date involving intravesical indwelling lidocaine-releasing devices.

Literature selection
To evaluate the published clinical trials of indwelling bladder lidocaine-releasing devices for IC/BPS, the PubMed, Google Scholar and the Cochrane Library databases were searched for articles published until May, 2022, with 'interstitial cystitis' OR 'painful bladder syndrome' AND 'intravesical' AND 'lidocaine' AND ('device' OR 'system') as the search terms. Two authors (TomofumiW and TSa) initially screened the search results independently, then worked together in cases requiring discussion until a consensus was reached. In addition, manual searches of original articles and reviews were performed to identify additional eligible studies.

Overview of IC/BPS
IC was first reported by Hunner in 1915 in a patient with bladder pain and ulcer (5). Since that time, the definition has changed several times, although IC/BPS is now defined as 'the condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases' (6,7). Patients with a characteristic ulcer (Hunner's lesion) are defined as Hunner-type IC (HIC); the remainder have bladder pain syndrome (BPS) (6,7). IC/BPS is painful, and thus the QoL of patients is markedly decreased (1).
The etiology of bladder pain has not yet been established, although one possible reason is that the loss of bladder urothelial function from various factors leads to the infiltration of urinary substances, such as potassium, which can induce bladder inflammation or nerve sensitization (8). There is another possible theory that claims that the pathogenesis of IC/BPS is an inflammatory change occurring in stromal tissues and involves the stimulation of sensory nerves by neurotransmitters or cytokines (neurologic inflammation). When acute peripheral inflammation activates nociceptors in the dorsal root ganglia, the production and release of neuropeptides, such as substance P, calcitonin gene-related peptide, or nerve growth factor (NGF), are increased (9,10). These neuropeptides lower the activation threshold of the central nerves (central nerve sensitization) and enhance the release of neuropeptides from the peripheral nerves (peripheral nerve sensitization), which trigger the increased permeability of the bladder mucosa and activate immune cells (mast cells) (11). These changes further accelerate peripheral nerve stimulation and inflammation, which may be the origin of unbearable bladder pain (12). Chronic pain syndromes, such as migraines, fibromyalgia, vulvodynia, chronic pelvic pain and irritable bowel syndrome, which are considered to involve central nerve sensitization and often co-exist, are now designated as central sensitivity syndrome (CSS) (13). Some patients with IC/BPS co-exist with CSS, which indicates the association between IC/BPS and CSS (14,15).
IC/BPS is more common among females and is considered a relatively rare clinical entity, with ~10-300/100,000 patients being diagnosed with IC/BPS (16,17). Previous studies have demonstrated that as many as 680/100,000 cases are possible/probable IC, and that ~2.70-6.73% of females meet the diagnostic criteria for IC/BPS (17,18). Thus, the incidence of potential IC/BPS is considered markedly higher than previously considered, highlighting the importance of seeking effective treatment.
A variety of treatments for IC/BPS, including conservative treatment, medical treatment, endoscopic surgery and the intravesical instillation of various drugs [dimethyl sulfoxide (DMSO), silver nitrile, phenol and lidocaine] have been suggested and tested (2)(3)(4). Compared to whole-body administration, intravesical instillation can deliver high concentrations of drugs locally to the bladder with reduced systemic toxicity and side-effects. A number of efforts have been made to maximize the drug concentration and exposure times in clinical studies since in vitro experiments involving human bladder cancer cell lines have revealed that the duration of exposure, as well as the concentration of a drug are crucial factors regarding cytotoxicity (19). In the majority of cases, the duration of drug exposure is limited to 2 h, and the instillations are repeated at fixed time intervals to maximize efficacy.

Pharmacological effects of lidocaine
Lidocaine is a local anesthetic and one of the most popular local anesthetics worldwide. Lidocaine was first synthesized by Löfgren in 1943 (20). Lidocaine demonstrates its anesthetic effects by inhibiting the generation and propagation of action potentials in peripheral nerve cells by non-specifically blocking the sodium channel. In addition, lidocaine suppresses delivery of polymorphonuclear cells to sites of inflammation by influencing the flux of sodium and calcium, which promotes membrane stability (21,22). Moreover, lidocaine reduces the release of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-1β and IL-8 from immunocytes and microglia (23). It has also been reported that nebulized lidocaine is beneficial in asthma therapy, which prevents eosinophilic inflammation (24). A prolonged nerve block by lidocaine can treat and prevent inflammatory hyperalgesia (25). Based on these results, it can be concluded that lidocaine not only reduces pain, but also exerts an anti-inflammatory effect and breaks the vicious cycle of IC/BPS from interaction between immunocytes and neurocytes by suppressing the migration or activation of immunocytes and by reducing the release of inflammatory cytokines.

Diagnostic significance of lidocaine in IC/BPS
As intravesical instillation can rapidly improve bladder pain, some studies have focused on the use of lidocaine for diagnostic purposes and for the categorization of IC/BPS. In a retrospective analysis in 2008, Fenton et al (26) regarded the pain relief from intravesical instillation of alkalized lidocaine (AL) as a reliable method for selecting patients who required cystoscopy and hydrodistension. They argued that the intravesical instillation of AL lowers the false-positive rate of hydrodistention (26). In fact, that study did not mention the actual false positive in detail (26). Nevertheless, that study still indicates the fact that there is a multidisciplinary chronic pelvic pain referral center that use lidocaine as an important diagnostic tool for IC/BPS (26).
In a retrospective chart review in 2009, Butrick et al (27) evaluated the treatment response rate of patients with bladder pain or dysfunction. In their study cohort that included 408 patients, one of the standard treatments was the weekly intravesical instillation of 200 mg non-alkalinized lidocaine, 20,000 units of heparin and 40 mg of triamcinolone (27). The treatment was repeated at least three times and was considered effective in 71% of patients. The intravesical instillation of lidocaine was most effective in patients whose chief complaint was consistent with a bladder pain disorder (73.7%) and the miscellaneous group (50%), which typically do not have bladder pain (27). In their study cohort, 120 patients who had suspected IC/BPS did not respond to the lidocaine cocktail intravesical instillation, even though 77% had a positive potassium sensitivity test; 51% were finally diagnosed with myofascial pain (27).
To evaluate the efficacy and safety of intravesical instillation of a 50% DMSO solution, Yoshimura et al (2) enrolled patients who exhibited pain relief with the intravesical instillation of lidocaine in a randomized, double-blind, placebo-controlled trial; the possible use of lidocaine in detecting patients with bladder-centric IC/BPS was also discussed.
The intravesical instillation of lidocaine is beneficial for the diagnosis of IC/BPS, not only by relieving bladder pain, but also by increasing bladder capacity during urodynamic studies. Offiah et al (29) reported changes in urodynamic findings and pain before and after the intravesical instillation of AL in 24 women who had previously been diagnosed with IC/BPS. Prior to enrollment, all participants completed the Central Sensitization Inventory (CSI) and Kings Health Questionnaire, and underwent urodynamic assessment. The participants were first asked to report pain during cystoscopy and post-void pain, then received an intravesical instillation of 20 ml 2% AL or normal saline. The solutions were instilled over a period of 20 min, after which pain scoring and the urodynamic study were repeated. Those who received lidocaine treatment exhibited a significant increase in the maximum bladder capacity, and those who failed to respond to treatment had a significantly higher co-morbid rate of CSSs (29). These results indicate that the intravesical instillation of lidocaine can be used to diagnose IC/BPS and evaluate the pathological findings (bladder-centric or originating in the central nervous system); however, additional data are warranted.

Therapeutic significance of lidocaine in IC/BPS
The intravesical instillation of lidocaine rapidly relieves bladder pain; however, the half-life is relatively short. Thus, considerable efforts have been made to extend the duration of action of lidocaine and increasing the analgesic effects.
Henry et al (30) reported the efficacy of the intravesical instillation of AL for IC/BPS and the pharmacokinetics in healthy volunteers and patients with IC/BPS. They reported that the optimal absorption of intravesical lidocaine was achieved when the bladder content pH was ~8.0 (30). Moreover, when considering the acidic pH of urine and lidocaine hydrochloride, the use of AL or a solution containing sufficient sodium bicarbonate is efficient to buffer the urine pH and optimize the absorption of intravesical lidocaine (30). The decreased mean pain score in 12 patients with IC/BPS and the safety of the intravesical instillation of 5 mg/kg lidocaine were also demonstrated (30). In the majority of clinical trials, lidocaine was administered alkalized or with sodium bicarbonate, based on these findings (31)(32)(33)(34)(35). Nickel et al (31) reported the efficacy of the intravesical instillation of AL in a randomized control trial. A total of 102 participants received an intravesical instillation of AL (200 mg) for 5 consecutive days. The safety of the treatment was demonstrated, and daily treatment was shown to significantly decrease pain (31).
In addition to alkalization, in some clinical trials, lidocaine was used in combination with heparin or hyaluronic acid, which are expected to repair the bladder glycosaminoglycan layer defects, and are thus predicted to provide relatively slow bladder pain relief. In 2005, Parsons (32) used lidocaine with sodium bicarbonate and heparin. Both 80 and 160 mg lidocaine exerted a rapid analgesic effect within 20 min of Instillation (32). Moreover, a single intravesical instillation with 80 mg lidocaine exerted a durable analgesic effect (>4 h), and in the group treated with 160 mg lidocaine three times per week for 2 weeks, 80% of the patients exhibited a significant improvement in symptoms lasting at least 48 h after the final treatment (32). Symptom relief lasted longer than the duration of the local anesthetic activity of lidocaine, suggesting that the solution suppresses neurologic inflammation. In 2012, Parsons et al (33) also demonstrated the efficacy of lidocaine with sodium bicarbonate and heparin in a double-blinded crossover trial. A total of 18 subjects were treated with 200 mg lidocaine, 50,000 IU heparin and sodium bicarbonate. The control group was treated with sodium bicarbonate alone. Compared with the control group, the lidocaine group exhibited a 35% reduction in pain and urinary urgency over a period of 12 h after the instillation (33).
Lidocaine is effective not only in reducing bladder pain, but also in relieving dyspareunia. Welk and Teichman (34) treated 57 patients with IC/BPS with the intravesical instillation of lidocaine, sodium bicarbonate and heparin three times a week for 3 weeks. All primary endpoints, including nocturia, voided volume, the Pelvic Pain Urgency Frequency score, and the Female Sexual Function Index pain domain score were significantly improved (34). Among the 23 participants with dyspareunia, 65% reported a >50% improvement in symptoms, with 13 participants (57%) claiming the resolution of dyspareunia (34).
As noted in the beginning of this chapter, the main difficulty with the intravesical instillation of lidocaine is the limited duration of the local anesthetic activity. Lv et al (35) compared treatment with 40 mg hyaluronic acid, 200 mg AL and hyaluronic acid + AL weekly for 8 weeks, then monthly for 4 months. Lidocaine exerted a favorable analgesic effect in the weekly phase of the treatment; however, in the monthly phase, no significant differences were observed in the hyaluronic acid group, and treatment was less effective in the AL group than in the hyaluronic acid group (35). In addition, the majority of the patients (14 of 15) in the AL group failed to complete the monthly treatment (35). That study was conducted over a longer period of time than the aforementioned studies and demonstrated that it was difficult to maintain the effects of lidocaine on a monthly basis, even though it was effective on a daily or weekly basis (35).

Intravesical indwelling lidocaine-releasing devices
To achieve a longer anesthetic effect of lidocaine, various indwelling bladder devices have been developed. The present study conducted a literature search as mentioned in the 'Literature selection' chapter above and identified a device (LIRIS™; TARIS Biomedical Lexington, LLC) which is the only indwelling bladder lidocaine-releasing device that has advanced to clinical trials (Table I) (36,37). Prior to LIRIS™, an intravesical indwelling oxybutynin-releasing device (UROS™; Situs Corporation, Houston, TX, USA) was developed (38,39). This horseshoe-shaped device was 10-15 cm in the largest diameter and released oxybutynin at a concentrate rate for up to 28 days (39). In a phase I/II trial, implantation with UROS™ resulted in an increase in bladder capacity of 100% in patients with a neurogenic bladder with a good tolerability (39). There have been no new reports, and UROS™ has not been used clinically to date, at least to the best of our knowledge. It has been suggested that the large device size causes irritation, and LIRIS™ was developed under the concept that the device size should be minimalized to avoid discomfort (36).
In 2011, Lee and Cima (40) developed a prototype device for LIRIS™. This pretzel-form intravesical lidocaine delivery device is comprised of a drug delivery unit and a retention frame and can be implanted and removed during cystoscopy (40). The delivery unit is a water-permeable tube with an orifice that functions as an osmotic pump and the retention frame prevents premature expulsion and irritation by maintaining the shape of the device (40). A total of 2 g lidocaine is crystallized and inserted into the tube (40). In an in vivo lidocaine exposure study involving male rabbits, the device was well-tolerated by the animals without any apparent change in voiding behavior, and the lidocaine concentration in the bladder tissue was maintained >0.1 µg/g during the 3-day period of device release, in contrast to the single instillation that exhibited an undetectably low plasma lidocaine level within 24 h (40).
Improving on this device, LIRIS™ was developed and tested in clinical trials (36,37). Its structure was similar to the device aforementioned and it was loaded with solid-formed lidocaine (40). In a single-blind, sham procedure-controlled phase I clinical trial with an empty LIRIS™ 200 mg device, the retention and tolerability of the device alone was tested (36). An empty LIRIS™ 200 mg device was placed in 7 out of 10 healthy participants by cystoscopy and 3 out of 10 participants underwent cystoscopy as a sham procedure (36). The device remained in the bladder for 14 days and exhibited preferable tolerability and safety (36). The majority of adverse events were associated with the cystoscopy procedure, and the most common treatment-related adverse event was dysuria and microscopic hematuria, which was associated with both treatment groups (36). The only severe adverse event was severe dysuria, which was observed in the sham-operated group (36).
To evaluate the safety, tolerability and efficacy of LIRIS™ for patients with IC/BPS, an open-label, ascending-dose phase Ib cohort study with LIRIS™ 200 mg and LIRIS™ 650 mg devices was conducted in women with moderate-to-severe IC/BPS (36). All patients had Hunner's lesions or glomerulations, and bladder pain (36). The patients were divided into two cohorts [LIRIS™ 200 mg (cohort 1, n=9) and LIRIS™ 650 mg (cohort 2, n=9)]; 2 patients participated in both cohorts (36). The participants kept the LIRIS™ device in the bladder for 14 days and were followed-up until 14 days following its removal. An additional 60-day follow-up of cohort 2 was implemented to evaluate the long-term safety and efficacy. Approximately 90% of the subjects experienced adverse events. The majority of these were mild or moderate in intensity and the most common adverse events were dysuria, bladder pain, hematuria and urethral pain (36). In total, three AEs were severe, although none were that severe to require the discontinuation of the trial (36). Both devices exhibited a clinically-meaningful relief of symptoms, including bladder pain, urgency, voiding frequency and improvement in all disease questionnaires [pain visual analog scale (VAS), urinary urgency VAS, O'Leary-Sant interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI)] (36). The cystoscopy findings also revealed the resolution of erythema and Hunner's lesions (5 out of 6 participants) (36). Moreover, 4 participants in cohort 2 experienced pain relief on day 28, and 3 participants reported continuous pain relief on days 60 and 90 (36).
In a 2-center, open-label phase Ib study, a LIRIS™ 400 mg device (not only 200 and 650 mg), also exhibited long-lasting improvement in lesions, pain, voiding frequency and the ICSI/ICPI score with favorable tolerance and safety (41). With these results, two phase II multicenter, randomized, double-bind, placebo-controlled studies were conducted to evaluate the efficacy of a LIRIS™ 400 mg device in female patients with HIC (study 001) and BPS without Hunner's lesions (study 002) (37). Both studies involved two treatment parts. Patients in the treatment 1 part were randomly divided into the LIRIS™ 400 mg device and placebo groups, and all participants who requested additional treatment were eligible to participate in the treatment 2 part, an open-label evaluation of a LIRIS™ 400 mg device as a second treatment at any time point from day 28 of follow-up to week 20 for study 001 and week 22 for study 002 (37). In total, 59 of 72 patients in study 001 were randomly divided and received treatment [LIRIS™/LIRIS™ (n=31), placebo/placebo (n=12) and placebo/LIRIS™ (n=16)]. A total of 11 patients were disenrolled from the study. In addition, 131 patients in study 002 were randomly dived and received treatment 1 [LIRIS™ (n=65) or the placebo (n=66)]. In total, 22 patients discontinued treatment and 98 patients received treatment 2 [LIRIS™ (n=50) or the placebo (n=48)]. In both studies, the frequency of treatment-emergent adverse events (TEAEs) was similar between the treatment groups (37). The most frequently reported TEAEs in the LIRIS™ group were dysuria, urinary tract infections, hematuria and bladder discomfort, and bladder pain in study 001, and dysuria, procedural pain, bladder discomfort, and nausea in study 002 (37). Study discontinuations due to TEAEs were low, and the majority of TEAEs were mild or moderate (37). The mean average bladder numeric rating scale (NRS) pain at week 4, which was the primary endpoint at the primary timepoint did not differ significantly between the groups in both studies. There was numerical pain relief in the LIRIS™ group in study 001 (37). There were no numerical or statistically significant differences between the study 002 groups with respect to NRS changes at any timepoint (37). There was a statistically significant decrease in the number of Hunner's lesions following treatment in study 001, although there was no significant difference between the LIRIS™ and placebo groups (37). In addition, the study 001 LIRIS™ group exhibited a greater decrease in the number of micturitions per day, although the difference was not significant (37). No numerical or statistically significant differences between treatments were observed in study 002 (37). There were no statistically significant or numerical differences between the treatments in urgency counts per day changes in either study (37). The authors of that study were of the opinion that the results of study 001 were not statistically significant due to the sample size, which was smaller than originally planned (37). They also believed that the validity of study 002 was unclear as there is no well-established and definitive test to identify the bladder as the source of the pelvic pain (37). In addition to LIRIS™, several devices have been developed, although the devices have not yet reached clinical trials, at least to the best of our knowledge. In 2021, a three-dimensional-printed elastomer-based intravesical delivery system was developed (42). Using stereolithography, the device obtained complex and precise form with high resolution and lidocaine was added to the liquid resin before printing (42). The solid device with 10 and 30% lidocaine demonstrated first-order release kinetics across 14 days in simulated urine with a shaking water bath (42).
In 2021, Kim et al (43) developed a device using another approach [a lidocaine-loaded indwelling urinary catheter (IUC)]. Kim et al (43) assembled a thin strand composed of poly(lactic-co-glycolic-acid) (PLGA) and lidocaine with an IUC by wrapping the surface to produce a L_PLGA_IUC. L_PLGA_IUC exhibited the durable release of lidocaine at pH 7.4 and 6.4. At pH 6.5, L_PLGA_IUC released lidocaine (~669.3 µg/cm) during the first day, after which lidocaine was released at a rate of ~5.0 µg/cm until 5 days, which was sufficiently high to demonstrate local anesthetic activity (43). In an in vivo animal cystometrogram (CMG) analysis, L_PLGA_ IUC decreased the bladder pressure and increased the interval of detrusor contractions; the effects were still present 3 days after the IUC insertion (43). In addition, efficacy was demonstrated, even in the cystitis-induced bladder (43). Moreover, the L_PLGA_IUC group of rats exhibited a significantly lower expression of pain-related inflammatory markers (NGF, cyclooxygenase-2 and IL-6) in bladder tissues (43).
As all of these devices are still in their infancy, there is limited evidence as regards their efficacy, and thus, they are not the first choice for IC/BPS treatment. If these devices significantly improve or a novel more effective device is developed, and further clinical trials are conducted, these devices may change the IC/BPS treatment strategy.

Conclusions and future perspectives
The intravesical instillation of drugs is conventionally performed in urology to deliver drugs directly and locally to the bladder mucosa. The diagnosis and treatment of IC/BPS is complex and difficult as it includes not only HIC with marked mucosal damage, but also NHIC (BPS) with no specific findings on cystoscopy and is also associated with CSS. Lidocaine has the potential to help in evaluating the IC/BPS phenotype, reduce pain through its analgesic effect, and break the pain cycle of neurologic inflammation through an anti-inflammatory effect. Currently, there are two major issues with the use of lidocaine: i) There are a limited number of previous studies describing the diagnostic significance of lidocaine; and ii) lidocaine lacks a long-term analgesic effect. If overcome these difficulties can be overcome with further research and the development of novel indwelling bladder devices, lidocaine may constitute a major advancement in IC/BPS treatment.