Current status of non-surgical treatments for Peyronie’s disease

Peyronie’s disease (PD), an acquired fibrotic disorder of the tunica albuginea, results in penile deformity, pain, and sexual dysfunction, substantially reducing quality of life in affected men (1). Variability in trial design, outcome definitions, and assessment methods has historically hindered the interpretation of nonsurgical interventions and the translation of statistical improvements into clinically meaningful outcomes (2). Contemporary clinical management prioritizes achieving “functional straightness”, commonly defined as a penile curvature of ≤30°, along with preservation of penile length, effective pain management, and restoration of satisfactory sexual function rather than complete anatomical correction (3). Clinically, PD is characterized by an active (acute) phase, defined by penile pain and dynamic curvature changes, followed by a stable (chronic) phase in which deformity plateaus (1-3). Accordingly, conservative management is generally prioritized during the active phase to control symptoms and potentially limit disease progression, whereas interventions targeting deformity are emphasized once the disease stabilizes (1-3). Within this framework, intralesional collagenase Clostridium histolyticum (CCH) represents the intervention with the strongest and most consistent evidence. Other approaches, such as interferon-α2b (IFN-α2b) and mechanical strategies, particularly penile traction therapy (PTT), provide additional but generally modest or adherence-dependent benefits. In contrast, oral or topical monotherapies rarely yield clinically meaningful curvature improvement when used alone (2). Key non-surgical options and their typical clinical use are summarized in Table 1. This editorial comment provides a concise, evidence-based overview of contemporary non-surgical treatment options for PD, emphasizing practical patient counseling and real-world considerations. Given the editorial scope, a formal systematic search was not conducted; instead, data from key randomized trials, high-quality systematic reviews, and major guideline updates were synthesized to provide a clinically oriented summary.

Over several decades, oral agents, including vitamin E, potassium para-aminobenzoate (POTABA), tamoxifen, colchicine, acetyl-L-carnitine, L-arginine, pentoxifylline, and coenzyme Q10, have demonstrated inconsistent or low-certainty effects on penile curvature when administered as monotherapy (1). A multicenter, placebo-controlled randomized trial of POTABA in men with disease duration <12 months demonstrated no significant improvement in pre-existing penile curvature, but showed a protective effect against the development of new curvature or deterioration of pre-existing curvature compared with placebo (4). A preliminary comparative trial reports symptomatic benefits of acetyl-L-carnitine over tamoxifen; however, its effects on penile curvature are minimal and not consistently reproducible, limiting its utility as a stand-alone deformity-modifying therapy (5). A double-blind, randomized trial demonstrated modest benefits of coenzyme Q10 in early chronic PD; however, its single-center design and lack of confirmatory studies restrict its role to an adjunctive rather than deformity-modifying therapy (6). Phosphodiesterase type-5 (PDE5) inhibitors support erectile function and sexual performance in men with concomitant erectile dysfunction; however, improved rigidity may increase the perceived severity of an existing deformity without reflecting structural progression, and these agents should not be considered stand-alone disease-modifying therapy for penile plaques (1,7). Retrospective comparative data suggest that daily low-dose tadalafil (5 mg) during the active phase may be associated with a lower short-term progression rate of penile curvature compared with observation alone (8). Evidence for oral combination regimens remains limited. Small observational studies and early clinical signals have explored PDE5 inhibitor-tamoxifen combinations, including vardenafil and tadalafil, during the active phase; these findings require confirmation in adequately powered controlled trials (9,10). Although oral pharmacotherapy is theoretically well-founded, its limited efficacy likely reflects the insufficient local concentrations within the tunical plaque to exert meaningful antifibrotic effects (1,2).

Topical and transdermal therapies—including verapamil gel and electromotive drug administration—are theoretically appealing but are limited by inconsistent plaque penetration, variable protocols, and uncertain clinical outcomes. Consequently, their routine use for curvature correction is not recommended outside clinical research settings (3). Oral and topical agents are best regarded as supportive therapies for pain, inflammation, or erectile function, while deformity-specific interventions should rely on treatments supported by stronger evidence (2).

Intralesional injection remains the cornerstone of nonsurgical PD management, with CCH as the only therapy demonstrated to provide clinically meaningful curvature reduction in large, randomized, placebo-controlled phase 3 trials (11). In the IMPRESS I and II studies, eight injections administered over four treatment cycles produced a mean curvature improvement of approximately 17° (34%) compared with approximately 9° (18%) with placebo, along with improvements in PD Questionnaire bother scores. These findings establish CCH as the on-label option for stable, non-ventral, and non-severely calcified penile curvatures typically ranging from 30° to 90° (11). Real-world data confirm these treatment effects and underscore the importance of standardized modeling protocols and strict adherence to post-injection instructions to minimize complications and maximize outcomes. Recent prospective real-world data indicate meaningful functional improvement, including restoration of penetrative intercourse in a substantial proportion of men treated with CCH using a modified regimen supplemented with vacuum erection device (VED) use (1,12). Adverse events are typically localized, including ecchymosis, edema, and pain, whereas corporal rupture is rare and mitigated by careful patient selection, education, and activity restrictions during treatment cycles (11). Notably, access to CCH is not uniform worldwide; the therapy is no longer available in Europe following market withdrawal, restricting availability across many European health systems (13,14). To address these feasibility barriers, modified ‘shortened’ protocols using fewer injections and clinic visits have been reported, yielding curvature improvements comparable to pivotal regimens and potentially reducing overall treatment duration and cost (15). Nevertheless, the high acquisition cost of CCH and the resource-intensive multi-visit regimen may limit access and completion of therapy in real-world practice (16,17).

Randomized trials demonstrate that IFN-α2b is superior to placebo in reducing penile curvature and pain in selected patients; however, the effect sizes remain modest compared with those of CCH. Flu-like systemic symptoms necessitate individualized risk–benefit discussions (2). Intralesional verapamil retains historical use and theoretical plausibility via calcium-channel blockade and antifibrotic signaling. However, controlled trials remain inconsistent and often underpowered, prompting caution in guidelines and a practical preference for alternative therapies when measurable straightening is the objective (3). Hyaluronic acid (HA) injections show favorable safety profiles and improvements in patient-reported outcomes in small comparative studies; however, curvature changes are minimal. Consequently, HA is best considered an adjunct option or reserved for selected scenarios pending confirmation in higher-quality randomized trials (3). Other intralesional agents, including platelet-rich plasma (PRP), thiocolchicine, corticosteroids, and cell-based products, remain investigational and should be restricted to clinical trials until robust efficacy and safety data are established (2). Preliminary cohorts and a phase 2 randomized, placebo-controlled crossover trial suggest that intralesional PRP is feasible and appears safe, but efficacy data remain limited and heterogeneous; therefore, PRP should remain restricted to clinical trials until standardized protocols and controlled outcomes are established (18,19).

Mechanical strategies serve as valuable adjuncts, particularly for preserving penile length and enhancing the corrective effects of intralesional therapy, with PTT demonstrating the most consistent noninvasive benefit when adherence is high (1). Traction induces collagen remodeling under sustained, low-intensity strain, and both observational and controlled studies report reductions in curvature and mitigation of length loss, with outcomes demonstrating dose-response relationships to daily wear time and device design. These findings underscore the need for realistic patient counseling regarding effort and comfort (2). Prospective data suggest that combining CCH with a structured penile traction protocol yields greater improvements in curvature and penile length than CCH alone. However, multicenter randomized trials with standardized adherence monitoring are required to quantify the incremental benefit across different plaque phenotypes (20). VEDs facilitate penile rehabilitation and length preservation but lack strong evidence for curvature correction, supporting their role as adjuncts rather than primary deformity-modifying therapies (1). Extracorporeal shockwave therapy (ESWT) has been evaluated in randomized and observational studies; recent systematic reviews and meta-analyses support short-term pain relief and, in some analyses, plaque size reduction, whereas effects on penile curvature remain inconsistent and generally modest, limiting ESWT primarily to analgesia when pain is the predominant symptom (21-23).

Combination strategies align with biological plausibility and real-world priorities, with CCH ± PTT representing the most widely adopted pairing to enhance curvature reduction and preserve length during injection cycles, provided patients adhere to daily device use (20). Additionally, rational multimodal regimens may incorporate PDE5 inhibitors for erectile dysfunction, short anti-inflammatory courses in painful acute presentations, and device-based adjuncts in motivated patients, while recognizing that definitive evidence supporting any single optimal combination remains limited (2). Given the increased complexity and cost of combination therapies, clinicians should establish clear success criteria, such as achieving functional straightness, restoring penetrative function, or resolving pain, and discontinue any components that do not contribute to these goals within a defined interval (3).

Effective counseling requires precise phenotyping, including assessment of disease phase (acute vs. stable), plaque location and degree of calcification, curvature severity and direction, presence of indentation or hourglass deformity, erectile function, and patient priorities regarding straightness, length, and sexual performance (1). In men with stable dorsal or dorsolateral 30°–90° curvature without prohibitive calcification who seek nonsurgical correction, CCH should be offered as the first-line, on-label therapy. Counseling should include a transparent discussion of expected mean outcomes, the need for multiple cycles, and the small but nonzero risk of corporal rupture (11). IFN-α2b represents a reasonable alternative for selected patients willing to accept systemic side effects and modest benefits, whereas intralesional verapamil or HA may be considered when CCH is unavailable or contraindicated, with clear counseling that the likelihood of achieving functional straightness is lower (2). Patients willing to dedicate daily time should be offered PTT as an adherence-dependent adjunct to enhance deformity correction and preserve length between injection cycles, with explicit instruction regarding device wear schedules and skin care (20). In men presenting with painful plaques during the stable phase, ESWT may provide analgesic benefit; however, improvements in curvature are unlikely, and additional deformity-directed therapy may be warranted (21).

Studies indicate a need for harmonized endpoints linking curvature and penile length with validated patient-reported outcomes, standardized photographic or three-dimensional measurement protocols, and digital adherence tracking during traction trials to better define dose–response relationships and real-world effectiveness (1). Comparative effectiveness studies of common combinations, such as CCH ± PTT or sequences incorporating HA or verapamil, are necessary to identify phenotype-specific responders, including men with indentation, hourglass deformity, or partial calcification, and to quantify the incremental benefit over single-modality care (2). Long-term follow-up incorporating cost and access analyses is critical for equitable implementation, given the resource demands associated with injection cycles and device use in community practice (3). Future investigations may explore preoperative CCH to reduce curvature severity before definitive surgical correction or prosthesis placement, with the objective of decreasing operative complexity in selected men with severe deformity (24,25). Given the relatively low incidence of PD and the heterogeneity of deformity phenotypes, multicenter collaborations and standardized prospective registries are essential for accruing adequately powered cohorts and producing generalizable, phenotype-stratified evidence (1-3). Until such evidence becomes available, clinicians should prioritize therapies with consistent, reproducible benefits, such as CCH for appropriate stable-phase deformities, selective IFN-α2b therapy, and adherence-dependent traction. Oral and topical agents should be employed primarily as adjunctive therapies, whereas surgical intervention should be reserved for men seeking or requiring definitive correction beyond the scope of nonsurgical care (1-3). In conclusion, non-surgical management of PD is optimally delivered through a phase-aware, preference-sensitive strategy that sets realistic goals, including functional straightness, pain control, and preservation of penile length and sexual function. This approach should prioritize therapies with the most reproducible benefit, such as CCH for eligible stable-phase deformities, selected intralesional alternatives, and adherence-dependent traction, while also recognizing real-world constraints related to access, cost, and treatment burden.

Acknowledgments

None.

Footnote

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