Low-energy extracorporeal shock wave therapy for interstitial cystitis/bladder pain syndrome: mechanisms, evidence, and translational perspectives—a narrative review

Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pelvic pain disease characterized primarily by bladder-related pain, accompanied by lower urinary tract symptoms including urinary frequency and urgency. The condition severely impairs patients’ quality of life (1,2), and epidemiological estimates vary considerably across populations (3,4). The multifactorial pathogenesis remains incompletely elucidated (5-7). Recent work from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network has further highlighted the marked clinical heterogeneity of IC/BPS. The Hunner lesion phenotype and widespread pain phenotype differ markedly in pathological mechanisms and treatment responses (7-9). Such phenotypic heterogeneity may introduce substantial confounding in clinical trials. Therefore, conventional clinical trials with broad enrollment criteriaoften fail to reach primary efficacy endpoints (10,11).

Clinical interventions for IC/BPS currently emphasize multimodal management. However, existing approaches, including oral medications, bladder instillations, and botulinum toxin injections, have limitations in terms of durability of response, consistency of benefit, and recurrence control. Most supporting evidence also has limited certainty (1,12). Accordingly, investigating non-invasive and repeatable strategies that may modulate local inflammation and tissue repair has potential translational relevance. Low-energy extracorporeal shock wave therapy (ESWT) has therefore been investigated as an experimental treatment for IC/BPS. Preclinical studies in cystitis and other tissue injury models suggest that shock wave-induced mechanotransduction may modulate inflammatory signaling, oxidative stress, tissue perfusion and repair, and nociceptive pathways (13-16). Some of these biological processes may also be relevant to selected IC/BPS phenotypes. However, the clinical evidence supporting low-energy ESWT for IC/BPS remains limited and heterogeneous. Although several studies have reported improvements in symptoms or biomarkers, the principal sham-controlled trial did not meet its primary endpoint, and subsequent studies were constrained by small sample sizes or uncontrolled study designs (14-16). More recently, a randomized trial found no additional clinical benefit from adjunctive intravesical botulinum toxin type A (BoNT-A) following low-energy ESWT (17). Accordingly, both the clinical efficacy and the mechanistic relevance of low-energy ESWT in IC/BPS remain uncertain and require further investigation.

Against this background, this narrative review examines the physical parameters, proposed mechanisms, and available clinical evidence for low-energy ESWT in IC/BPS. We distinguish evidence derived from human studies, IC/BPS-specific animal models, and indirect mechanistic studies conducted in other tissues or disease models. Particular attention is given to the gap between biological plausibility and demonstrated clinical efficacy, as well as to priorities for phenotype-informed patient selection, treatment parameter standardization, core outcome reporting, and rigorous sham-controlled trial design. The aim is to clarify the current investigational status of low-energy ESWT in IC/BPS and to identify the evidence needed to support its potential translation into routine clinical practice. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0595/rc).

Methods

A literature search of PubMed/MEDLINE and the Web of Science Core Collection was conducted to identify relevant studies published between January 1, 2010 and May 31, 2026. The search strategy and study selection process are summarized in Table 1.

Fundamentals of low-energy ESWT in IC/BPS

Physical principles and device characteristics

Low-energy ESWT is a non-invasive physical modality that delivers short-duration acoustic pressure pulses generated by an external device to target tissues through a coupling medium. Shock waves are characterized by a rapid rise to a positive-pressure peak, a short pulse duration, and a subsequent negative-pressure phase. These acoustic characteristics distinguish shock waves from the lower-amplitude, more periodic waveforms typically used in diagnostic ultrasound (18-20). In contrast to the high-energy shock waves used for lithotripsy, low-energy ESWT is delivered at lower energy flux densities (EFD) intended to induce biological responses without tissue fragmentation. The resulting mechanical stimuli may initiate cellular mechanotransduction and downstream biological responses. In the bladder microenvironment, these responses have been proposed to influence tissue repair, immune regulation, and nociceptive signaling (13,16-20).

The biological effects of low-energy ESWT are influenced by device-specific physical characteristics. EFD alone is therefore insufficient to characterize or compare treatment protocols. Focused shock waves are generated using electrohydraulic, electromagnetic, or piezoelectric systems and concentrate acoustic energy within a defined focal zone at a selected tissue depth, allowing energy to be delivered to a specific target region. By contrast, radial pressure waves are generated by ballistic mechanisms, reach their maximum pressure at the applicator surface, and attenuate rapidly with increasing tissue depth, which may limit their suitability for deeper tissue targets. Radial pressure waves are therefore physically distinct from focused shock waves (18,20). Although published IC/BPS studies generally report basic treatment parameters, reporting of device specifications and focusing characteristics remains inconsistent. Given the technical variability among ESWT devices, future studies should consistently report the device model, shock-wave generation technology, and focusing characteristics to improve reproducibility and cross-study comparability (18,20).

Delivery approaches and treatment parameters

In published clinical studies, low-energy ESWT for IC/BPS has generally been administered transcutaneously through the suprapubic region. Patients are typically placed in the supine position, ultrasound coupling gel is applied, and the treatment applicator is positioned over the suprapubic region corresponding to the bladder. Moderate bladder filling is generally maintained to facilitate anatomical localization and treatment targeting (14-17).

Across published clinical studies, commonly used protocols have employed an EFD of 0.25 mJ/mm², a pulse frequency of 3 Hz, and 2,000–3,000 pulses per session, administered once weekly for 4–8 consecutive weeks (14-17). Table 2 summarizes the treatment protocols, study designs, primary outcomes, and key limitations of these studies. Although these regimens appear to be well tolerated in the short term, the optimal EFD, pulse number, treatment frequency, and course duration remain uncertain. Whether optimal treatment parameters differ across IC/BPS phenotypes also remains unknown, as phenotype-stratified treatment responses have not been prospectively evaluated. Future trials should therefore prespecify key clinical phenotypes when assessing dose–response relationships and durability of response (14-20).

Molecular mechanisms of low-energy ESWT in IC/BPS

Low-energy ESWT has been proposed to influence several biological processes relevant to IC/BPS, including mechanotransduction, inflammatory and oxidative stress pathways, urothelial barrier function, angiogenesis and tissue repair, and nociception-related signaling (5,6,15,21-25). Most mechanistic evidence is derived from preclinical models, whereas direct mechanistic evidence in patients with IC/BPS remains limited (15). Table 3 summarizes the major mechanistic domains and supporting evidence, and Figure 1 provides an integrated overview of the proposed mechanisms.

Figure 1 Proposed multi-target biological mechanisms of low-energy ESWT relevant to IC/BPS. Dashed arrows indicate low-energy ESWT-induced mechanical stimulation; solid arrows indicate regulatory relationships; rightward arrows indicate downstream effects. ↑ and ↓ denote upregulation/activation and downregulation/inhibition, respectively. ESWT, extracorporeal shock wave therapy; IC/BPS, interstitial cystitis/bladder pain syndrome; ROS, reactive oxygen species.

Mechanotransduction and early cellular responses

Low-energy ESWT is thought to initiate biological responses through mechanotransduction, whereby mechanical stimuli generated by acoustic pressure waves, including transient shear stress and cavitation-related effects, are transduced into intracellular signals (20,23,24). Experimental studies in non-bladder cell and tissue models suggest that shock wave exposure may engage membrane-associated mechanosensors, including integrins and caveolin-1, with subsequent ATP release and activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (Akt), and endothelial nitric oxide synthase (eNOS) signaling (23,24). These signaling events may contribute to cell survival, vascular responses, and tissue remodeling.

Anti-inflammatory and immunomodulatory effects

Inflammatory mechanisms appear to be more prominent in Hunner-type interstitial cystitis (HIC), which is characterized by urothelial denudation and lymphoplasmacytic infiltration, whereas bladder inflammation is less consistently observed in non-Hunner interstitial cystitis (NHIC) (5,7). In cyclophosphamide (CYP)-induced cystitis models, low-energy ESWT was associated with reduced inflammatory and oxidative stress signaling, together with decreases in nociceptive behavior and cystometric abnormalities in rodents (22,25). Mechanistic studies further suggested the involvement of G protein-coupled receptor 120 (GPR120)-dependent inhibition of transforming growth factor-β-activated kinase 1 (TAK1)/nuclear factor-κB (NF-κB) signaling (26). More recent preclinical studies associated low-energy ESWT with altered expression of miR-146b-5p and miR-21-5p, lower levels of IL-1β and IL-6, and partial restoration of the tight junction protein ZO-1 (27). Taken together, these findings suggest that low-energy ESWT may modulate inflammatory signaling and influence urothelial barrier integrity through multiple pathways.

Antioxidant and anti-apoptotic effects

Oxidative stress has been implicated in urothelial dysfunction, inflammation, and sensory sensitization in IC/BPS (6). In a CYP-induced rat cystitis model, low-energy ESWT was associated with reductions in oxidative stress markers, including inducible nitric oxide synthase (iNOS), NADPH oxidase 1 (NOX1), NADPH oxidase 2 (NOX2), and oxidized proteins (25). In a hydrochloric acid (HCl)-induced rat cystitis model, low-energy ESWT was associated with a lower Bax/Bcl-2 ratio, reduced cleaved caspase-3 expression, and decreased terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) positivity, without a clear change in cytochrome c level (28). These findings suggest that low-energy ESWT may attenuate oxidative stress and modulate mitochondrial apoptosis-related signaling in experimental cystitis models.

Urothelial barrier repair and permeability modulation

Urothelial barrier dysfunction, including loss of umbrella cells, altered glycosaminoglycan (GAG) coverage, and reduced junctional protein expression, has been implicated in bladder-centric IC/BPS (5,6,29). In a CYP-induced rat cystitis model, low-energy ESWT was associated with partial restoration of ZO-1, increased E-cadherin expression, and lower IL-1β and IL-6 levels (27). Preclinical studies also suggest that low-energy ESWT may transiently increase urothelial permeability, facilitating intravesical BoNT-A delivery and liposome retention in rats (27,30). However, a randomized clinical trial found no additional clinical benefit of intravesical BoNT-A following low-energy ESWT compared with saline (17). These findings suggest that transient increases in urothelial permeability and restoration of barrier-related proteins may represent distinct biological effects of low-energy ESWT.

Angiogenesis and tissue regeneration

Low-energy ESWT has been associated with angiogenic and proliferative signaling in experimental models outside IC/BPS (20,23,24). In endothelial cells, ESWT increased VEGF and eNOS expression and activated ERK1/2 and Akt signaling through caveolin-1- and β1-integrin-related mechanotransduction (20,23). Other experimental studies have linked low-energy ESWT-induced ATP release and purinergic signaling to ERK1/2-mediated proliferation and tissue repair (24,32). Collectively, these studies support a potential role for ERK/Akt/eNOS-, VEGF-, and ATP-related signaling in angiogenesis and tissue repair following low-energy ESWT.

Analgesic and neuromodulatory effects

IC/BPS pain is heterogeneous and may involve urothelial dysfunction, mast-cell activation, neurogenic inflammation, and sensitization of bladder afferents through NGF- and TRP-related pathways (5,6). In a uroplakin 3A (UPK3A)-induced autoimmune cystitis mouse model, low-energy ESWT increased suprapubic mechanical response thresholds and improved urinary frequency and urine output, accompanied by lower TNF-α and NGF levels and reduced inflammatory-cell infiltration (31). These findings suggest that modulation of inflammatory and neurotrophic signaling, including TNF-α and NGF pathways, may contribute to the analgesic effects observed in experimental cystitis models (5,6).

Evidence landscape and translational relevance

Evidence for low-energy ESWT in IC/BPS spans several levels of translational relevance, including human clinical studies, IC/BPS-specific animal models, related bladder dysfunction models, and mechanistic studies in non-urological systems. Human studies provide the most direct evidence of clinical effects, whereas preclinical and cross-tissue studies contribute mechanistic and biological support. This evidence hierarchy helps identify both the current level of clinical support and the areas requiring further translational validation.

Human clinical evidence

Current published human clinical evidence is primarily represented by four clinical reports (14-17), with heterogeneity in study design, comparator, and follow-up duration; detailed study-level findings are summarized in Table 2.

Chuang et al. (14) did not demonstrate a significant between-group benefit for the prespecified 4-week O’Leary-Sant symptom score (OSS) primary endpoint. Nevertheless, at 12 weeks, a ≥3-point reduction in visual analog scale (VAS) was more frequent with low-energy ESWT than with sham treatment (57.1% vs. 19.0%; P=0.01), while global response assessment (GRA) ≥2 remained nonsignificant between groups (47.6% vs. 28.6%; P=0.20). Collectively, these findings support a potential pain-response signal in a subset of patients, but do not establish a consistent benefit across the broader IC/BPS symptom burden.

Shen et al. (15) reported greater 4-week reductions in OSS and pain VAS with low-energy ESWT than placebo (−5.4 vs. −0.9; P=0.01 and −2.0 vs. −0.6; P=0.02, respectively), whereas GRA response did not differ significantly. Exploratory urinary biomarker changes were also observed, but the overlapping cohort limits interpretation of these findings as independent confirmatory evidence.

In the prospective single-arm study by Jhang et al. (16), pain VAS, Interstitial Cystitis Symptom Index (ICSI), and Interstitial Cystitis Problem Index (ICPI) decreased from 5.07 to 2.17, 12.87 to 7.87, and 11.80 to 7.27, respectively, at 12 months, whereas no significant changes in urodynamic parameters were detected at the 1-month post-treatment assessment. However, attribution of these symptom changes to low-energy ESWT alone remains uncertain because the study lacked a control group and 73.3% of participants received concomitant IC/BPS therapy.

More recently, Jhang and Kuo (17) compared low-energy ESWT plus intravesical BoNT-A with low-energy ESWT plus saline in a randomized double-blind trial. The primary endpoint—the between-group difference in OSS change from baseline to 4 weeks after treatment—was not met (−1.3 vs. −1.9 points; P=0.73; adjusted P>0.99). No statistically significant between-group differences were observed in VAS, ICSI/ICPI, GRA, or objective outcomes after multiplicity adjustment; at 2 months, GRA ≥2 was achieved in 32.0% versus 50.0% of patients (P=0.19; adjusted P=0.58). The modest magnitude of the within-group changes warrants caution in interpreting statistical significance as clinically meaningful improvement. Because both randomized groups received low-energy ESWT, the controlled comparison primarily evaluates the incremental effect of intravesical BoNT-A rather than the efficacy of low-energy ESWT versus no low-energy ESWT.

Overall, current human evidence provides a preliminary signal of short-term pain improvement in some patients, whereas effects on broader symptom domains and objective bladder outcomes remain less consistent. Larger sham-controlled trials are needed to determine the magnitude and clinical meaningfulness of treatment effects and to identify patient subgroups most likely to benefit. Available studies also suggest favorable short-term tolerability, while larger cohorts and longer follow-up are required to characterize uncommon or delayed adverse events.

IC/BPS-specific animal models

Currently, preclinical evidence for low-energy ESWT efficacy in IC/BPS is based primarily on three rodent cystitis models: CYP-induced, HCl-induced, and UPK3A-induced models. As summarized in Table 3, these studies collectively support the potential multi-target local reparative effects of low-energy ESWT. For anti-inflammatory and cytoprotective effects, low-energy ESWT attenuates inflammatory responses in bladder tissue, reduces oxidative stress, and inhibits cellular apoptosis (22,25). In experimental models, low-energy ESWT was associated with improved mitochondrial function and preservation of tissue ATP levels, changes that may contribute to urothelial recovery (28). In terms of symptomatic improvement, these microenvironmental changes were associated with increased bladder capacity and reduced immune-mediated visceral pain behaviors in specific animal models (31).

These IC/BPS-relevant animal models provide disease-specific mechanistic support for the anti-inflammatory, cytoprotective, urothelial, and analgesic effects of low-energy ESWT. Because current models primarily reproduce selected components of IC/BPS rather than its full chronic and phenotypically heterogeneous clinical spectrum, further human studies are needed to determine whether these biological effects correspond to clinically meaningful symptom improvement (8,10). Future translational studies may also use these models to identify candidate biomarkers and mechanistic endpoints for prospective clinical evaluation.

Indirect evidence from bladder dysfunction models

Beyond the IC/BPS-specific models mentioned above, low-energy ESWT has demonstrated bladder-protective and functional benefits in other lower urinary tract dysfunction (LUTD) models. These include ketamine-induced bladder injury, chronic ischemic bladder dysfunction, and ovarian hormone deficiency-related overactive bladder models (20,33-35). In these studies, low-energy ESWT has been reported to improve impaired bladder function by enhancing local perfusion, attenuating tissue inflammation, and promoting regeneration. Nonetheless, the pathological mechanisms and therapeutic targets of these models differ from those of IC/BPS. These related LUTD models broaden the biological evidence for the bladder-protective effects of low-energy ESWT, particularly in relation to tissue perfusion, inflammation, and regeneration. Because their underlying pathology differs from IC/BPS, the relevance of these mechanisms should next be evaluated in IC/BPS-specific experimental systems and phenotype-defined clinical studies.

Supporting evidence from non-urological models

Additional mechanistic evidence relevant to low-energy ESWT comes from studies of wound repair, vascular endothelium, skeletal muscle, and peripheral nerve injury. These studies have linked low-energy ESWT to ATP release and ERK1/2-mediated proliferative signaling, enhanced endothelial viability and angiogenic signaling, myocyte differentiation, and nerve fiber remodeling (20,23,24,32,33). Together, these cross-tissue findings identify candidate pathways that may be relevant to bladder repair and pain modulation. Further bladder-specific and clinical studies are needed to determine which of these pathways are engaged in IC/BPS and whether they are associated with treatment response.

Clinical translation of low-energy ESWT in IC/BPS

Future clinical development of low-energy ESWT in IC/BPS should focus on five domains: phenotype-informed patient selection, protocol standardization, harmonized outcome assessment, prospective safety monitoring, and combination therapy (Figure 2).

Figure 2 A proposed five-dimensional framework for the clinical translation of low-energy ESWT in IC/BPS. BoNT-A, botulinum toxin type A; EFD, energy flux density; ESWT, extracorporeal shock wave therapy; GAG, glycosaminoglycan; GRA, global response assessment; IC/BPS, interstitial cystitis/bladder pain syndrome; NRS, numerical rating scale; PRP, platelet-rich plasma; UTI, urinary tract infection; VAS, visual analog scale.

Patient selection: who is most likely to benefit?

IC/BPS is a heterogeneous disorder that includes bladder-centric and systemic pain phenotypes (8-11). Because low-energy ESWT is delivered locally to the suprapubic bladder region, treatment response may differ according to disease phenotype (14-17). Future trials should therefore incorporate prespecified phenotyping at baseline, including Hunner lesion status, anesthetic bladder capacity, pelvic floor tenderness, and the extent of widespread pain (8-10,36). These variables should be incorporated into planned stratified or subgroup analyses rather than explored only post hoc. Urinary biomarkers may be collected as exploratory correlates, although none are currently sufficiently validated for routine treatment selection (11). In patients with Hunner lesions, guideline-recommended lesion-directed therapy should remain standard care, with low-energy ESWT evaluated only as an investigational adjunct (1,7).

Protocol standardization: how should low-energy ESWT be delivered?

Methodological and procedural differences across published studies include device characteristics, pulse number, targeting strategy, bladder filling status, treatment duration, and comparator conditions (14-17), which may complicate reproducibility and cross-study comparisons. Future studies should use prespecified, reproducible treatment protocols and consistently report the device model and shock-wave source, focusing characteristics, EFD, pulse frequency and number, treatment site, bladder filling status, session schedule, and operator experience (14,16-20,37,38). Dose-ranging studies are needed to define the optimal treatment intensity and course. Sham-controlled trials should use appropriately matched sham procedures with adequate blinding, while concomitant therapies should be prespecified and documented (39-43).

Outcome assessment: what should be measured?

Outcome selection should be aligned with the clinical phenotype and intended treatment target. Pain and urinary outcomes should be assessed separately, with clinically meaningful thresholds and assessment time points prespecified (44-46). Pain-focused trials may use VAS or NRS together with global response measures, whereas trials targeting storage symptoms should include voiding diaries assessing daytime and nocturnal frequency, voided volume, and functional bladder capacity (14,44). Urinary biomarkers may be incorporated as exploratory or secondary endpoints, while clinical efficacy should remain anchored in patient-reported outcomes (15,17,44,47).

Safety monitoring: what risks should be considered?

Published IC/BPS studies have reported few short-term adverse events during or following low-energy ESWT. In the sham-controlled trial, mild suprapubic pain occurred in two patients and transient hematuria in one patient, while urinary retention, infection, and other major complications were not consistently reported across the available studies (14,16,17). However, the small sample sizes and limited harms reporting preclude reliable assessment of uncommon or delayed adverse events (14,16,17,48).

These observed events should be distinguished from eligibility and diagnostic precautions. Active urinary tract infection should be excluded before enrollment or treatment, whereas unexplained hematuria or suspected bladder stones or malignancy should be appropriately evaluated (1,7). Study-specific exclusion criteria should not be interpreted as established contraindications to low-energy ESWT (16). Future trials should prospectively record adverse events of interest, serious adverse events, and treatment discontinuations in accordance with CONSORT Harms 2022, with longer follow-up to assess delayed events (14,16,17,48). Informed consent should state that low-energy ESWT remains investigational for IC/BPS and that its long-term safety is uncertain (7,16,17).

Combination therapy: when is low-energy ESWT best used as an adjunct?

Low-energy ESWT should be evaluated as an adjunct within phenotype-directed multimodal care rather than as a replacement for established treatment (7,49). In patients with Hunner lesions, guideline-recommended lesion-directed therapy should remain the priority. In non-Hunner, bladder-predominant phenotypes, future trials may evaluate low-energy ESWT within structured multimodal strategies, whereas pelvic floor or widespread pain phenotypes may require multidisciplinary management (10,36,46,49). Combination strategies, including intravesical BoNT-A, platelet-rich plasma (PRP), GAG-based agents, and liposomal formulations, should be evaluated in controlled designs that can determine their incremental benefit over low-energy ESWT alone (17,49-53).

Conclusions

Low-energy ESWT has a biologically plausible rationale for IC/BPS, with preclinical studies supporting several relevant biological mechanisms and current human evidence suggesting a preliminary short-term pain-response signal. Effects on broader symptom domains, voiding outcomes, and long-term benefit require further confirmation. Future research should prioritize adequately powered, sham-controlled trials with standardized treatment protocols, prespecified phenotype stratification, harmonized outcome assessment, and longer follow-up, particularly according to Hunner lesion status and bladder-predominant versus widespread pain phenotypes. Such studies are needed to determine whether clinically meaningful and durable benefit exists, which patients, if any, are most likely to benefit, and the long-term safety profile. Until stronger clinical evidence is available, low-energy ESWT should remain an investigational adjunct and should not replace phenotype-directed standard care.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0595/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0595/prf

Funding: This research was funded by the Healthcare Talents Youth Program of Shanghai Pudong New Area (grant No. 2024PDWSYCQN-04), the National Key Clinical Specialty Construction Project (grant No. 10000015Z155080000004), and the Key Discipline Development Initiative of the Shanghai Health System (grant No. 2024ZDXK0043).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0595/coif). The authors have no 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.

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