Peyronie’s disease patients with pain: a post hoc analysis of the IMPRESS I/II studies

Introduction

Peyronie’s disease (PD) is characterized by the hyperplastic formation of collagen-containing fibrous scar tissue beneath the penile skin, which can cause curved and painful erections, potentially shortening erect penile length (1-3). As a result, PD can have profoundly negative physical and psychological effects on individuals and their partners, including emotional distress, depression, sexual dysfunction, and relationship problems (4-6). PD is traditionally categorized into 2 phases: acute (hereafter referred to as “active”) and chronic (hereafter referred to as “stable”). However, the clinical definitions and distinctions between the phases vary across the literature, contributing to ambiguity in determining the phase of a patient’s disease (1,7-9).

The American Urological Association (AUA) guidelines outline fluctuating symptoms, particularly the presence of penile and/or glandular pain or discomfort, as characteristic of the active phase but provide little guidance on specific timeframes for symptom duration (3,8,9). Historically, the literature has associated penile pain and worsening deformity (e.g., worsening penile curvature) with the active phase, with time from symptom onset to the end of the active phase ranging between <3 and 18 months (Table 1) (3,7-9). Although there may be academic utility in temporally categorizing PD, it may unnecessarily limit or postpone treatment options for patients suffering from the condition since some treatments are not recommended during the early stages of PD (1,3,8). Recently, Trost and colleagues (10) conducted a retrospective analysis of 1,098 men with penile deformity to address the ambiguity in PD phases, to better define subtypes, and to clarify distinctions between active and stable stages. The analysis found that although penile pain did occur more commonly in the active phase of disease, it was not an independent predictor and should not be used as a defining characteristic of active vs. stable disease. Additionally, results demonstrated that the duration of the active phase varied depending on the PD subtype, which helped explain the historically wide variability (3–18 months) of active-phase duration in the existing literature.

Collagenase clostridium histolyticum (CCH) is the only Food and Drug Administration (FDA)-approved nonsurgical treatment option for PD. CCH is composed of 2 collagenases (AUX-I and AUX-II) that act by hydrolyzing collagen types I and III in fibrous cords or plaques and down-regulating genes, cytokines, and growth factors related to PD, thereby improving symptoms (11). CCH has been approved in the United States since 2010 for the treatment of adults with Dupuytren’s contracture (DC) with a palpable cord and since 2013 for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30° (11). The IMPRESS (Investigation for Maximal Peyronie’s Reduction Efficacy and Safety Studies) I and II studies evaluated the efficacy and safety of CCH among 832 male patients diagnosed with PD for more than 12 months with evidence of stable disease (12).

One large multi-institutional real-world study with 918 PD patients (13) and several small-series studies (14-16) evaluated CCH treatment in active-phase PD. All studies demonstrated similar results in men with active disease, with no higher rates of adverse events reported, suggesting that CCH may be safely and effectively used in this cohort.

The current study sought to expand upon the existing literature of CCH use in men with active-phase disease/penile pain by examining data from the IMPRESS I and II cohorts (12). The study objectives were to evaluate whether the presence or absence of penile pain at baseline influenced CCH treatment efficacy (improvement in penile curvature) and, among those with penile pain, whether the disease duration (12–18 vs. >18 months) influenced treatment outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0280/rc).

Methods

This study was a secondary analysis of de-identified data from a previously conducted clinical trial. The IMPRESS I (NCT01221597) and IMPRESS II (NCT01221623) studies enrolled adult men with PD at 64 clinical sites across the United States and Australia between September 2010 and March–April 2012. Eligible participants had stable dorsal or dorsolateral penile curvature of 30°–90° and were randomized in a 2:1 ratio to receive CCH or placebo. Participants received up to 4 treatment cycles, each consisting of 2 intralesional injections administered 24–72 hours apart, with investigator-performed penile plaque modeling following the second injection of each cycle. Outcomes were assessed through 52 weeks, including standardized measurements of penile curvature, Peyronie’s Disease Questionnaire (PDQ) domains, and safety end points (12).

A post hoc analysis of pooled data from these 2 phase 3 randomized, double-blind trials of CCH to treat PD was conducted (12). In this analysis, patients were stratified by those who reported Any Pain vs. No Pain across each pain measure.

Pain was evaluated using investigator-assessed and patient-reported measures of penile pain. Investigator-assessed measures include penile pain on palpation (flaccid penis) or erection, using a 5-point Likert scale. The No Pain group included those reporting pain as “none”, and the Any Pain group included those reporting pain as “mild”, “moderate”, or “severe”. Patient-reported measures included 4 items from the PDQ (17). Three of the items (PDQ 7–9) assessed penile pain when the penis was not erect over the last 24 hours, the last time it was erect, and during intercourse. The items were scored on an 11-point numeric rating scale (NRS), with 0 being “no pain or discomfort” and 10 being “extreme pain or discomfort”. The No Pain group included those scoring 0 on all 3 items and the Any Pain group included those scoring 1–10 on any of the 3 items. The fourth item (PDQ 10) assessed the degree of bother from pain or discomfort felt in an erect penis on a 5-point Likert scale, with the No Pain group including those who selected “no issue” or “not at all bothered”. The Any Pain group included those who reported bother as “a little bit”, “moderately”, “very”, or “extremely”.

Given that timeframe guidance for treatment is lacking for those experiencing pain (Table 1), an additional subgroup analysis stratifying patients with Any Pain by disease duration (12–18 vs. >18 months) was performed. Because the original IMPRESS I/II trials only enrolled men with PD duration ≥12 months, patients with <12 months of symptoms were not available for inclusion in this analysis.

The primary efficacy end point of the phase 3 IMPRESS studies was percentage change in penile curvature at week 52 from baseline. For the analyses presented here, outcomes were summarized as mean change in penile curvature, expressed in both percent and degrees, with variability described using standard deviations and precision estimated using confidence intervals. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Statistical analysis

Comparisons between groups were conducted using unadjusted analyses, applying 2-sample t-tests to compare mean outcomes across predefined pain status and disease duration subgroups. Analyses were restricted to CCH-treated patients with complete baseline and week 52 penile curvature data; no additional imputation for missing data was performed.

Results

Baseline demographic and clinical characteristics

A total of 364 CCH-treated patients had both baseline and week 52 measurements and were included in this analysis. Baseline demographic and clinical characteristics of CCH-treated participants, stratified by pain status across investigator-assessed and patient-reported pain measures, are summarized in Table 2. Across pain groupings, baseline characteristics, including age, race, penile curvature, disease duration, and plaque severity, were generally similar. The overall average age (standard deviation, SD) was 57.2 (8.0) years, with most patients being White (95.6%). Average disease duration (SD) was 4.1 (4.4) years, and baseline penile curvature (SD) was 50.2° (14.3°; Table 2).

Overall penile curvature outcomes

Among the 364 CCH-treated men included in this post hoc analysis, mean penile curvature improvement from baseline to week 52 ranged from approximately 32% to 37% across pain definitions and disease duration subgroups.

Penile curvature at week 52: No Pain vs. Any Pain groups

Results demonstrated similar penile curvature improvements after CCH treatment among those who reported Any Pain vs. No Pain at baseline. Across all 4 measures of penile pain, pain on erection (Figure 1), pain on palpation (Figure 2), PDQ 7–9 (Figure 3), and PDQ 10 (Figure 4), no clinically meaningful differences were observed between groups (35.0–36.7% improvement for the No Pain group vs. 32.2–33.9% improvement for the Any Pain group; P=0.14–0.65).

Figure 1 Improvement of penile curvature from baseline by percent (left) and degrees (right) as stratified by penile pain on erection (N=364). Patients were included in the No Pain group if investigators recorded their pain as “none”. Patients were included in the Any Pain group if investigators recorded their pain as “mild”, “moderate”, or “severe”. Improvement from baseline (%): P=0.26 (95% CI, −9.966, 2.686). Improvement from baseline (°): P=0.39 (95% CI, −4.631, 1.831). Error bars indicate standard error. CI, confidence interval.

Figure 2 Improvement of penile curvature from baseline by percent (left) and degrees (right) as stratified by penile pain on palpation (N=364). Patients were included in the No Pain group if investigators recorded their pain as “none”. Patients were included in the Any Pain group if investigators recorded their pain as “mild”, “moderate”, or “severe”. Improvement from baseline (%): P=0.65 (95% CI, −12.176, 7.656). Improvement from baseline (°): P=0.94 (95% CI, −4.861, 5.261). Error bars indicate standard error. CI, confidence interval.

Figure 3 Improvement of penile curvature from baseline by percent (left) and degrees (right) as stratified by PDQ 7–9 (N=364). Patients scoring pain as 0 to all 3 questions were included in the No Pain group. Patients scoring pain >0 to any of the 3 questions were included in the Any Pain group. Improvement from baseline (%): P=0.43 (−8.761, 3.761). Improvement from baseline (°): P=0.58 (−4.097, 2.297). Error bars indicate standard error. CI, confidence interval; PDQ, Peyronie’s Disease Questionnaire.

Figure 4 Improvement of penile curvature from baseline by percent (left) and degrees (right) as stratified by PDQ 10 (N=363). One patient was excluded due to missing PDQ-10 data. Patients reporting “no issue or not at all bothered” by pain were included in the No Pain group. Patients reporting “a little bit bothered”, “moderately bothered”, “very bothered”, or “extremely bothered” by pain were included in the Any Pain group. Improvement from baseline (%): P=0.14 (95% CI, −10.504, 1.544). Improvement from baseline (°): P=0.13 (95% CI, −5.474, 0.674). Error bars indicate standard error. CI, confidence interval; PDQ, Peyronie’s Disease Questionnaire.

Penile curvature at week 52: Any Pain group by disease duration

When stratifying men with Any Pain group by disease duration, curvature improvements were similar among those with shorter disease duration (12–18 months; 21.8–34.8% improvement) compared with longer duration (>18 months; 31.4–36.8% improvement; P=0.20–0.95) (Table 3).

Discussion

This post hoc analysis of clinical trial data from the IMPRESS studies was designed to investigate whether the presence of penile pain influenced outcomes associated with CCH treatment; and among those with Any Pain, whether disease duration also influenced outcomes. Key findings from the current study reaffirm that penile pain and baseline disease duration among those with pain do not negatively impact CCH outcomes. These observations provide evidence that further supports findings from existing publications that have highlighted the safety and efficacy of CCH use in early-, acute-, or active-phase PD populations. The current findings are supported by robust analyses, which include subgroup analyses of various baseline PD durations and multiple measures of penile pain in a variety of contexts. Importantly, all participants were drawn from the IMPRESS phase 3 trials, which enrolled only men with PD duration ≥12 months, so the present data reflect an exclusively chronic-phase population.

One of the challenges in evaluating penile pain is the lack of standardized assessment methods. Men with PD may experience pain in the flaccid state, with erections, on direct palpation of the plaque, with intercourse, as a generalized/nonspecific complaint, as a persistent or variable symptom, or as a combination of the above. Additionally, although pain has often been described as being synonymous with active-phase disease and ongoing inflammation, to the authors’ knowledge, there have never been any studies that have provided data to support this belief.

Given these issues, this study sought to evaluate several distinct types of penile pain to associate the symptoms with differences in CCH outcomes. However, despite evaluating multiple investigator-assessed and patient-reported measures of pain, none of the analyses demonstrated any correlation with CCH outcomes. These results are important not only as an independent finding, but also because they provide additional support to the recent publication by Trost et al. (10), which noted that penile pain was not a reliable predictor for PD progression or stability. These observations would suggest that historical beliefs surrounding penile pain as a marker for disease activity are unfounded and not supported by contemporary literature. Furthermore, the AUA PD guideline definition for active-phase disease does not incorporate terms related to penile pain in its nomenclature (3).

Because penile pain is likely a poor surrogate for active-phase disease, the current study also sought to analyze the impact of CCH on the basis of differing PD disease durations among men experiencing PD-related pain. Specifically, men in the study with Any pain were classified as either being 12–18 months from disease onset (shorter disease duration) or >18 months (later-duration chronic disease). In comparing the 2 cohorts, no differences in CCH outcomes were observed. Although the existing dataset did not include men who had PD <12 months and therefore cannot address true acute/early-phase PD, examining 12–18 vs. >18 months among pain-positive men provides an exploratory assessment of whether earlier vs. later chronic disease duration influences CCH response. These analyses suggest that even among men who might be perceived as “active” on the basis of ongoing pain, CCH outcomes were similar regardless of whether they were 12–18 or >18 months from symptom onset.

The current study findings provide additional support to previously published series examining similar themes, while extending these observations into an exclusively chronic-phase (≥12-month) IMPRESS population. Specifically, in the largest multi-institutional cohort (N=918), Nguyen et al. (13) defined acute PD as symptom duration ≤6 months and found no significant differences in curvature improvement, or treatment-related adverse events compared with men with longer-duration stable disease. In a separate single-center series (n=162), the same group defined acute PD as duration ≤12 months with penile pain, and observed similar curvature, erectile function, and safety outcomes vs. stable-phase patients (15). Reports from smaller cohorts, including Yang (n=49; active disease defined as symptom duration <12 months or subjective deformity change) (14) and Hu et al. (n=229; acute phase defined by ≤6-month duration and by ≤12 months with pain) (16), likewise reported no statistically significant differences in curvature response or adverse events between men with acute/active and chronic/stable PD; however, only Hu et al. provided formal statistical comparisons between these groups.

In contrast to these studies, which included true acute/early-phase cohorts (≤6 or ≤12 months), the present analysis is restricted to men with PD duration ≥12 months, and the 12–18 vs. >18-month comparison should therefore be interpreted as an exploratory evaluation of shorter vs. longer chronic-phase disease within the Any Pain subgroup rather than as a definitive acute- vs. stable-phase comparison.

These observations and data are relevant clinically, as clinicians may be reticent to refer or treat individuals in the active phase of disease based on a belief that CCH is administered using criteria similar to those reserved for surgical interventions. Additionally, some medical insurers may deny coverage for CCH in men who currently have penile pain and/or are <12 months out from disease onset. However, as noted earlier, each of these practices is not based on sound medical principles or data and has no scientific or FDA-label restriction basis at the present time.

The current study does have several limitations, including the post hoc nature of the analysis, absence of data on men <12 months, and lack of data to subclassify men into PD. As a result, our findings should be interpreted within a chronic-phase (≥12-month) IMPRESS population, and the 12–18 vs. >18-month comparison within the Any Pain subgroup should be viewed as exploratory, with limited ability to inform true acute/early-phase PD. However, the study does exhibit several strengths, including its multi-institutional nature, large sample size, breadth of penile pain measures, and robust data reporting.

Conclusions

The current study demonstrates similar curvature improvements among men with PD who were treated with CCH, regardless of baseline penile pain status or disease duration. In this post hoc analysis of phase 3 trial data, findings are consistent with other published series that have also demonstrated no differences in outcomes based on patient baseline pain status or active- vs. stable-phase disease classification. Taken together, these findings suggest that, among men with PD who are candidates for collagenase therapy, penile pain and disease duration should not be considered contraindications to treatment or primary factors in clinical decision-making when determining expected outcomes.

Acknowledgments

The authors thank Gregory J. Kaufman, MD, for his contributions during the initial development of this manuscript. Medical writing and editorial assistance were provided by Pam Sinicrope, MPH, DrPH, and Stephen Bublitz, ELS, of the Propel Division of Woven Health Collective, LLC (New York, NY, USA). This manuscript was prepared according to the International Society for Medical Publication Professionals’ “Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3”. This work was presented in part at Sexual Medicine Society of North America 2025 Annual Fall Scientific Meeting, October 9-12, 2025, Grapevine, TX, USA.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0280/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0280/prf

Funding: This study was supported by Endo USA, Inc. (a Keenova Therapeutics Company).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2026-0280/coif). J.N.M. reports consulting/advisory roles for Boston Scientific Corporation and Endo USA, Inc. (a Keenova Therapeutics Company); and investigator roles for Endo USA, Inc. (a Keenova Therapeutics Company). G.A.B. reports consulting/advisory roles for Endo USA, Inc. (a Keenova Therapeutics Company). J.P.T., M.A., T.R., J.A. and S.P. report employment with Endo USA, Inc. (a Keenova Therapeutics Company). The other author has 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

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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