Pharmacotherapy for bladder spasm and irritative lower urinary tract symptoms associated with intravesical therapy for bladder cancer: a review of available evidence

Introduction

Detrusor muscle spasms, commonly referred to as “bladder spasms”, are a frequent complication following urologic procedures (1-4). Clinically, these spasms manifest as pelvic cramping, urgency, and dysuria, often leading to significant periprocedural discomfort. Involuntary bladder contractions may result in voiding or leakage around a urethral catheter if present. Bladder spasms have been defined as sudden, intermittent, and short-lasting pain localized to the bladder region in patients who were previously asymptomatic on routine analgesia (5). Bladder spasms have been reported following various urologic interventions, including cystoscopy, transurethral resection, catheterization, and intravesical therapy (1-4).

Beyond their impact on patient-reported satisfaction, bladder spasms can adversely affect procedural outcomes (3,5,6). For instance, spasms and other irritative lower urinary tract symptoms (LUTS) have been associated with treatment discontinuation and delays in intravesical therapy for bladder cancer (6). Moreover, premature expulsion of therapeutic agents due to involuntary bladder contractions may raise concerns from patients and clinicians about treatment efficacy and is of particular interest given a number of recent and pending drug approvals for novel intravesical therapies.

Bacillus Calmette-Guérin (BCG), the first-line intravesical immunotherapy for non-muscle-invasive bladder cancer (NMIBC), carries a relatively low risk of expulsion despite its known irritative properties (6). However, newer intravesical agents, such as the gene therapy nadofaragene firadenovec, present unique challenges. Nadofaragene firadenovec, an adenoviral vector-based gene therapy, has recently been approved for the treatment of BCG-refractory NMIBC. The drug is a first-in-class intravesical gene therapy agent, and its active ingredient includes a surfactant (Syn3) to help the adenoviral vector cross through the bladder’s glycosaminoglycan (GAG) layer (7). In addition, the drug is shipped frozen and must be thawed before instillation. Discharge around the catheter during instillation and bladder spasms were among the most common study drug-related treatment-emergent adverse events, seen in 25% and 16% of the phase 3 study participants, respectively (8). The United States Food and Drug Administration (FDA) recommend pretreatment with anticholinergic medications to reduce bladder spasms in these patients (4). Nevertheless, evidence supporting the short-term efficacy of anticholinergics for spasm prevention in this context remains limited, warranting further investigation.

This review examines the pathophysiology of bladder spasms and irritative LUTS in the context of intravesical therapy for NMIBC. We evaluate pharmacologic strategies for spasm prevention and LUTS management, with particular emphasis on pretreatment approaches for patients receiving novel intravesical therapies such as nadofaragene firadenovec. By synthesizing current evidence and clinical practice insights, this review aims to provide practical recommendations for optimizing therapeutic outcomes, minimizing treatment-associated complications, and highlighting gaps in the existing literature to guide future research.

Bladder spasms: pathophysiology of overactive bladder (OAB)

Although the pathogenesis of bladder spasm secondary to urologic procedures has not been exclusively studied, it shares key pathophysiological mechanisms with detrusor overactivity (DO), as both conditions involve involuntary detrusor muscle contractions. DO is the most commonly identified cause of OAB symptoms, affecting more than 75% of individuals with OAB (9,10).

While the precise mechanisms underlying DO remain incompletely understood, several hypotheses have been proposed:

• Myogenic mechanisms: spontaneous detrusor activity may arise from intrinsic muscle dysfunction, with recent investigations highlighting the role of detrusor uninhibited contractions in bladder storage symptoms (11).
• Neurogenic dysfunction: abnormal neural signaling has been implicated in both idiopathic and neurogenic forms of DO, suggesting a central role for neural pathways in DO (12).
• Urothelial involvement: the urothelium has been recognized as an active participant in detrusor contraction. During bladder filling and stretch, adenosine triphosphate and other mediators released from the urothelium modulate afferent nerve activity and smooth muscle contraction (12,13).

Additionally, inflammatory responses, direct irritation of the bladder mucosa, bladder outlet obstruction, and bladder wall hypoperfusion are believed to contribute to OAB pathogenesis (14). Given the multifactorial nature of these mechanisms, effective management of OAB and related bladder spasms necessitates a multifaceted therapeutic approach.

Intravesical therapy for bladder cancer: advantages and challenges

The standard of care for NMIBC consists of transurethral resection of the bladder tumor (TURBT) followed by intravesical BCG therapy for patients with intermediate- and high-risk disease (15). BCG remains the first-line immunotherapeutic agent and the most effective modality for reducing NMIBC recurrence and progression (15). In patients with BCG-unresponsive disease, radical cystectomy is the recommended definitive treatment. However, many individuals are either medically unfit for surgery or elect to pursue bladder-preserving alternatives. To date, the FDA has approved four alternative therapies for patients who are ineligible or unwilling to undergo cystectomy: systemic pembrolizumab, intravesical valrubicin, and, most recently, intravesical nadofaragene firadenovec and nogapendekin alfa inbakicept (16-18). Although additional treatment modalities exist, their use remains off-label.

Intravesical chemotherapy and immunotherapy have demonstrated efficacy in reducing NMIBC recurrence and progression following TURBT (6,19). One of the primary advantages of intravesical therapy is its localized delivery, which minimizes systemic adverse effects. The urinary bladder, functioning as a natural reservoir that can be accessed via urethral catheterization, serves as an optimal target for regional therapy (19). However, direct exposure of the bladder mucosa to chemotherapeutic and immunotherapeutic agents is associated with significant irritative effects and LUTS. These symptoms range from mild dysuria and discomfort to severe bladder spasms, which may result in premature drug expulsion, as well as more severe complications such as cystitis and hematuria (4,6).

Pathophysiology and incidence of LUTS associated with current approved intravesical therapy agents for NMIBC

BCG

BCG has been the cornerstone of intravesical therapy for NMIBC since its introduction in the 1970s (20). It remains the most effective adjuvant therapy for reducing recurrence and progression in patients with NMIBC (15). Extensive research has been conducted on the mechanisms of action of BCG and its associated adverse effects, with LUTS and cystitis-like symptoms being the most frequently reported side effects (21). Despite variability in defining BCG-related LUTS, studies estimate their occurrence in 50% to 91% of patients (21,22). The most frequently reported BCG-related LUTS include urinary frequency, urgency, pelvic pain, and dysuria (23). Such symptoms typically arise within 2 to 4 hours following BCG instillation. While symptoms often resolve spontaneously within 48 hours, their severity can be significant enough to necessitate postponement of subsequent instillations (21).

Although BCG-induced LUTS are common, their underlying pathophysiology remains incompletely understood. Several potential mechanisms have been proposed, drawing parallels between BCG cystitis and interstitial cystitis/bladder pain syndrome. These include:

• Bladder afferent sensitization: Sensitization of peripheral neuronal afferents occurs when they are exposed to noxious stimuli resulting in exaggerated sensory firing (24). Such noxious stimuli can include bacterial infection, inflammation, cytotoxic chemicals, and tissue destruction (25). Bladder noxious stimuli were found to significantly enhance bladder afferent firing to bladder distension and recruit a population of “silent nociceptors” to turn into mechanosensitive receptors sensitizing the bladder to physiologic stimuli. Such sensitization mediates bladder spasms, urgency, frequency, and pelvic pain (24).
• Inflammation-induced hypersensitivity: BCG triggers a localized massive immune reaction within the bladder mucosa, characterized by influx of neutrophils, macrophages, and dendritic cells into the bladder wall, with expression of multiple cytokines in the urine and bladder tissues hours after its instillation (26). Such an intense inflammatory response carries the potential of sensitizing bladder afferents mediating the irritative LUTS after BCG (25,26).
• Urothelial barrier dysfunction: The disruption of urothelial barrier permeability has been described as one of the major predispositions to bladder pain syndrome/interstitial cystitis (27). While the evidence of BCG intravesical therapy insult on the urothelial barrier is still lacking, it was suggested that the severe inflammatory reaction in the bladder after exposure to BCG may deplete the GAG layer, resulting in a “leaky” epithelium allowing contact of the bladder interstitium to the noxious contents in urine promoting irritative LUTS (28).

Based on such potential mechanisms, therapeutic modalities to mitigate BCG LUTS symptoms have been proposed and tested.

Targeting bladder spasms and afferent sensitization

The rationale for targeting bladder spasms to manage urgency and frequency associated with BCG is based on OAB management. Anticholinergics and beta 3 agonists have been studied for the management of BCG-associated LUTS. There is only low-quality evidence supporting the use of oxybutynin in patients receiving BCG. In a randomized controlled trial (RCT) of 50 BCG-naïve patients, oxybutynin 10 mg daily was associated with higher incidence of irritative LUTS, mainly urinary frequency and burning micturition, versus placebo (29). The treatment group also experienced higher rates of anticholinergic side effects, such as dry mouth and constipation. However, when oxybutynin was compared to phenazopyridine and celecoxib, it significantly reduced BCG LUTS compared to placebo yet was less effective than celecoxib and had more side effects than placebo (30). In a meta-analysis of different trials assessing pharmacotherapy to treat BCG LUTS, oxybutynin was inferior to celecoxib, prulifloxacin, ofloxacin, and levofloxacin in reducing urinary frequency, but showed no significant improvement over placebo in reducing urgency symptoms (23). On the other hand, mirabegron 25 mg daily was effective in reducing irritative LUTS associated with BCG in a single RCT of 160 patients (31). In this study, mirabegron significantly reduced OAB symptom score, nocturia, and urge urinary incontinence, although the reduction in dysuria was not statistically significant.

Targeting inflammatory process associated with BCG

Selective nonsteroidal anti-inflammatory drugs (NSAIDs), such as celecoxib, have shown efficacy in improving urinary urgency, frequency, and dysuria related to intravesical BCG compared to placebo (30,32). Celecoxib, a cyclooxygenase 2 (COX-2)-selective NSAID, has been demonstrated to reduce the inflammatory response triggered by BCG, thereby mitigating LUTS. In a RCT, celecoxib significantly reduced urinary frequency, urgency, and dysuria compared to placebo, making it a promising option for managing BCG-induced LUTS (30). When assessed in a meta-analysis for pharmacotherapy to treat BCG LUTS, celecoxib was one of the most effective therapies to reduce urinary frequency, urgency, pelvic pain, and dysuria (23). Despite this, evidence supporting celecoxib for BCG LUTS comes from only a few studies with low sample size. Moreover, long-term use of celecoxib with BCG should be approached with caution due to potential cardiovascular risks. The Coxib and traditional NSAID Trialists’ (CNT) Collaboration meta-analysis of over 350,000 randomized patients demonstrated that selective COX-2 inhibitors, including celecoxib, were associated with a significant increase in major vascular events, particularly myocardial infarction, as well as an increased risk of vascular death compared with placebo. The excess risk was suggested to be dose-dependent and related to long-term use of this class of medications, highlighting that while short courses of celecoxib for BCG-related LUTS may be safe, extended use could expose patients to higher risks of cardiovascular accidents (32).

Antituberculous antibiotics have also been investigated to reduce the inflammatory response of BCG. Pretreatment of patients receiving intravesical BCG with fluoroquinolones (ofloxacin, levofloxacin, prulifloxacin) has demonstrated some effect in reducing BCG adverse effects including LUTS (33-36). However, concerns related to the effect of such medications on the therapeutic efficacy of BCG and the oncologic outcome of therapy have limited their use.

Targeting urothelial barrier dysfunction

Several strategies have been explored to restore urothelial integrity and the GAG urothelial barrier in patients receiving BCG based on:

• Intravesical hyaluronic acid (HA) and chondroitin sulfate (CS): HA/CS are considered an effective GAG replenishment therapy for patients with interstitial cystitis. Intravesical administration of HA/CS in combination with BCG has been used in 20 patients with BCG-refractory cystitis. Data have showed improvement of LUTS in these patients (37). In a more recent prospective, multicenter study of 118 patients, sequential combined intravesical instillations of HA/CS after every BCG session significantly reduced storage symptoms, urinary frequency, and pelvic pain versus BCG alone (38). This improvement was maintained through the 6-month follow-up.
• Oral pentosan polysulfate (PPS): PPS, an FDA-approved treatment for interstitial cystitis, has also been investigated for its role in restoring the urothelial barrier. In a retrospective cohort of 217 patients, those receiving oral PPS alongside BCG had significantly lower discontinuation rates due to adverse effects compared to those receiving BCG alone (39). However, concerns about potential side effects, such as retinal maculopathy, have limited its widespread use.

Valrubicin (Valstar)

Valrubicin, an intravesical, chemotherapeutic agent approved for the treatment of BCG-refractory NMIBC, is associated with irritative LUTS, including dysuria as the most common side effect, seen in 77%; bladder spasms with urinary urgency and frequency were seen in 23% (40). These symptoms may be due to the direct cytotoxic effects of valrubicin on the bladder mucosa, which can lead to local inflammation and irritation. However, the incidence and severity of LUTS with valrubicin are generally lower compared to those observed with BCG therapy. Valrubicin was associated with a milder adverse event profile, with fewer patients discontinuing treatment due to intolerable LUTS compared to BCG (40).

To date, there are very few studies specifically investigating strategies to manage LUTS associated with valrubicin. The limited data available suggest that management typically relies on symptomatic treatment, including the use of anticholinergics (e.g., oxybutynin) to reduce bladder spasms and analgesics (e.g., phenazopyridine) to alleviate dysuria. These approaches are extrapolated from studies on other intravesical therapies, such as BCG, where anticholinergics and analgesics have demonstrated efficacy in mitigating irritative symptoms (23,30). However, the absence of robust clinical trials focusing on valrubicin-specific LUTS management underscores the need for further research to establish evidence-based guidelines.

Nadofaragene firadenovec (Adstiladrin)

Nadofaragene firadenovec is an adenoviral vector-based gene therapy approved by the FDA in 2022 for the treatment of BCG-unresponsive NMIBC. Early results showed that nadofaragene firadenovec is well tolerated; the most frequently reported side effects were irritative LUTS (4).

Pathophysiology of nadofaragene firadenovec-induced LUTS

The mechanism of nadofaragene firadenovec-induced LUTS was not exclusively studied to date; however, the antitumor effect of nadofaragene firadenovec is based on a strong immune and inflammatory response within the bladder mucosa (7). The adenoviral vector delivers the interferon alfa-2b (IFNα2b) gene to the bladder uroepithelial cells’ DNA, stimulating the sustained production of IFNα2b which exerts direct cytotoxic effect resulting in hypoxia and necrosis of cancer cells (4). In addition, IFNα2b exerts direct and indirect immunomodulation stimulating T cells and natural killer cells’ destruction of cancer cells. This inflammatory response is characterized by the release of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor-alpha, which sensitize bladder afferent nerves and increase detrusor muscle activity, leading to symptoms such as urgency, frequency, and bladder spasms (4,41). Additionally, the mechanical irritation from the adenoviral vector itself may contribute to urothelial barrier dysfunction. Furthermore, the use of Syn3, a polyamide surfactant that promotes the transduction of the adenoviral victor across the GAG layer of the bladder wall, may further exacerbate LUTS. It is worth noting that a fraction of patients receiving nadofaragene firadenovec comprise those with chronic BCG cystitis who suffer from chronic LUTS before starting nadofaragene firadenovec therapy, which may exacerbate their symptoms.

The most frequently reported adverse event was discharge around the catheter during instillation (25% of patients), bladder spasms (16%), micturition urgency (15%), and dysuria (12%) (8). These symptoms typically emerge within the first 24–48 hours following instillation and may persist for a median of 2 days, depending on the severity of the inflammatory response. Notably in the single-arm open-label trial by Boorjian et al. (4), the bladder spasms and discharge around the catheter resulted in two of 110 patients in the study population discontinuing therapy. The FDA recommends pretreatment with anticholinergic medications, such as oxybutynin, to mitigate bladder spasms and reduce the likelihood of premature drug expulsion (4); however, more studies are needed to evaluate the outcome of pharmacotherapy for LUTS in this group of patients.

Nogapendekin alfa inbakicept (Anktiva)

Nogapendekin alfa inbakicept is an interleukin 15 superagonist designed to enhance the immune response against cancer cells and is administered intravesically in combination with BCG for the treatment of BCG-unresponsive NMIBC with carcinoma in situ, with or without papillary tumors (18). Results from the QUILT-3.032 trial demonstrated that nogapendekin alfa inbakicept combined with BCG therapy was commonly associated with LUTS, including dysuria, urinary frequency, and hematuria, which are anticipated with intravesical BCG instillation. To date, no studies have evaluated the best management of LUTS associated with nogapendekin alfa inbakicept therapy, although supportive measures using anticholinergics and anti-inflammatory medications are often used based on its association with BCG therapy.

This lack of evidence for managing adverse urinary symptoms with newer intravesical agents underscores the need to consider therapeutic strategies that have been studied in related contexts. In practice, urologists often extrapolate symptomatic management from other conditions where bladder irritation and spasms are common, such as after urologic instrumentation or catheterization. Furthermore, expert opinion on the symptomatic management of LUTS associated with newer agents offers valuable guidance.

Are there other modalities to manage bladder spasms and irritative LUTS associated with intravesical therapy?

While the available evidence on intravesical therapy-associated bladder spasms and irritative LUTS primarily comes from studies related to BCG therapy, measures used to reduce bladder spasms and irritative LUTS following urologic procedures and urethral catheterization—commonly referred to as catheter-related bladder discomfort (CRBD)—in addition to management strategies for patients with interstitial cystitis/bladder pain syndrome can provide valuable insights into other pharmacotherapy options for reducing bladder irritation.

For instance, anticholinergic agents such as oxybutynin, tolterodine, and solifenacin have demonstrated efficacy in reducing CRBD in various urologic procedures. Studies have shown that these medications can significantly decrease the incidence and severity of CRBD when administered preoperatively or postoperatively. For example, oxybutynin, has been effective in reducing CRBD after radical prostatectomy and percutaneous nephrolithotomy (PCNL) (42,43). Similarly, tolterodine has been shown to reduce the incidence of CRBD by 25% when administered preoperatively (44). Moreover, solifenacin has also been effective in reducing CRBD symptoms after TURBT (45).

Furthermore, antiepileptic drugs such as gabapentin and pregabalin have been evaluated for their role in preventing postoperative CRBD. Gabapentin, when administered orally before surgery, has been shown to reduce the incidence and severity of CRBD in patients undergoing procedures such as TURBT and PCNL (46,47). Pregabalin, another antiepileptic, has also demonstrated efficacy in reducing CRBD, particularly in patients undergoing spine surgery, although it was associated with increased sedation (48).

Finally, oral and rectal diazepam (49), intravesical diamorphine, intravesical botulinum toxin, and pudendal nerve block have been described in rare reports for relieving bladder spasms and CRBD in patients when other measures fail (49-52).

These pharmacotherapy options, while primarily studied in the context of CRBD, may offer potential benefits for managing bladder spasms and irritative LUTS associated with intravesical therapy, particularly in cases where catheter irritation is a significant concern. However, further research is needed to explore their efficacy and safety specifically in the context of intravesical therapy.

Expert opinion regarding best approaches to prevent spasm induced by intravesical therapy

Based on the above review it is clear that bladder spasm can cause patient discomfort and negatively impact the optimal delivery of intravesical therapy, although high-level evidence to support ideal prophylaxis is lacking. Pending such evidence, we now present suggested approaches based on pharmacology and clinical experience.

Supportive measures

Simple nonpharmacologic interventions should not be forgotten as they can have an equally large impact without side effects. Patients should restrict fluids for a few hours before intravesical instillation, which will reduce bladder filling while the medication is in situ. For drugs that are delivered frozen such as nadofaragene firadenovec, following thawing, the drug should ideally be brought to full room temperature before use to reduce afferent activation from cold stimulation. Finally, some of our nurses report use of a heating pad on the lower abdomen may reduce spasm during therapy.

Anticholinergics and beta 3 agonists

While daily, long-term use of anticholinergics and beta-3 agonists remains a cornerstone in the management of OAB symptoms, evidence supporting their “as needed” (PRN) use particularly in the setting of intravesical therapy-related LUTS is limited.

Pretreatment with anticholinergics has been described in the management of bladder spasms during the perioperative period of lower urinary tract surgeries and in CRBD (42-44). These studies have typically employed oxybutynin (5 mg every 8 hours or once) and tolterodine (2 mg once) before procedures to reduce bladder spasms. However, the onset of action and time to clinical effect for anticholinergics vary between compounds and outcome measures, ranging from several days to months (53,54). Based on available data, fast-acting anticholinergics with shorter half-lives may offer the most practical option for pretreatment before intravesical therapy instillation.

While anticholinergics are commonly associated with systemic side effects such as dry mouth, constipation, and potential cognitive risks, beta-3 agonists generally avoid these adverse effects. Mirabegron has demonstrated effectiveness in relieving BCG-induced irritative LUTS when used daily throughout the course of intravesical therapy (31). However, to date, no clinical trials have evaluated the efficacy or feasibility of beta-3 agonists, including mirabegron, for PRN use.

Table 1 summarizes the pharmacokinetic properties of common anticholinergics and beta-3 agonists and their potential suitability for PRN use in the context of intravesical therapy.

Transrectal valium

Rectal diazepam has recently been explored as an alternative strategy for mitigating bladder spasms and improving drug retention during intravesical therapy, particularly in patients receiving nadofaragene firadenovec for BCG-unresponsive NMIBC (56). Unlike traditional anticholinergic agents, which primarily target muscarinic receptors, rectal diazepam acts through central gamma-aminobutyric acid-mediated pathways, modulating both sensory afferent input and detrusor contractility. A retrospective cohort study at Mayo Clinic demonstrated a 23.6% absolute reduction in bladder spasms and a 24.6% improvement in drug retention with rectal diazepam pretreatment (10 mg, administered 15 minutes before instillation) compared to conventional premedication regimens or no pretreatment (56).

Despite its potential benefits, the use of transrectal diazepam for bladder spasm prophylaxis is not without limitations. The lack of standardized dosing protocols and prospective clinical trials assessing its efficacy in intravesical therapy remain barriers to widespread adoption. Moreover, while rectal administration reduces some of the sedation and cognitive side effects associated with oral benzodiazepines, careful patient selection is warranted, particularly in older adults at risk for falls or respiratory depression. While no serious adverse events related to diazepam were reported in the aforementioned retrospective study, one patient experienced fatigue attributed to diazepam pretreatment (56). This finding underscores the importance of cautious administration and appropriate counseling, particularly in older patients. Future research should focus on defining optimal dosing strategies, comparative efficacy against standard anticholinergic therapies, and the potential role of transrectal diazepam in multimodal bladder spasm prevention regimens. If validated in prospective trials, transrectal diazepam may offer a novel and effective strategy to improve intravesical therapy outcomes while minimizing systemic side effects associated with traditional oral agents.

Conclusions

Bladder spasms represent a clinically meaningful barrier to effective delivery of intravesical therapy and can contribute to patient discomfort, premature drug expulsion, and discontinuation of treatment. Although high-level evidence to guide prophylaxis is limited, supportive, pharmacologic, and emerging strategies may provide symptomatic benefit. Tailoring management to individual patient needs while balancing therapeutic benefit with potential adverse effects remains essential. Further research is needed to establish evidence-based approaches for symptom management in this evolving therapeutic setting.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-483/prf

Funding: This work was supported by Ferring Pharmaceuticals.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-483/coif). All authors report administrative support for this manuscript was provided by Ferring Pharmaceuticals. V.M.N. has served as a consultant or received research funding from Ciox Health. M.T. has received royalties or licenses from Endoluxe and honoraria for roles on the steering committees for POTOPSCO (AstraZeneca) and LEGEND (enGene); he gave a bladder cancer lecture to the commercial team and holds stock/stock options at ImmunityBio; he has participated in a scientific advisory board for Protara Therapeutics. D.S. is an employee of Ferring Pharmaceuticals, Inc. S.V. has served as a consultant for Medtronic and BlueWind. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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