What published research says about Peyronie's Disease
Evidence-based research package for Peyronie's Disease. Guide, Evidence Reference, Practice Gap, and a CARE Brief you can print and bring.
Drop #1·Published April 2026·55+ peer-reviewed studies·How we verify →
At a glance
New finding
Two Phases
Active disease means curvature is still changing; stable means no change for three or more months. Treatment options differ by phase, and pain resolution alone does not confirm stability.
Dorsal curvature responds best to collagenase (CCH); ventral and lateral respond less consistently. Volume-loss deformities appear in roughly 65% of patients and are often missed during routine assessment.
Collagenase (CCH) plus daily traction. RestoreX is the most-studied traction device, with an RCT showing meaningful curvature improvement at 30–90 minutes per day.
The only double-blind RCT of intralesional verapamil showed exactly 0.0° change in curvature. Published protocols are weekly to biweekly; longer intervals are unprecedented.
What the research showed about Brian's verapamil prescription
Brian was given verapamil injections for his Peyronie's disease. The only double-blind controlled trial showed exactly zero curvature change. Every controlled trial was negative.
What the research showed about Brian's treatment schedule
Every published verapamil protocol used six or more injections at weekly to biweekly intervals. No published study has ever used a three-month interval — the schedule Brian was on.
There is an FDA-approved injection specifically indicated for Peyronie's disease — collagenase clostridium histolyticum (Xiaflex). It was never mentioned to Brian, not once, in months of visits.
Brian is preparing for a second-opinion appointment, armed with the evidence above. He's bringing a filled-in CARE Brief with questions cited directly from the research — the same CARE Brief any PD patient can customize for their own visit.
Here’s how the research played out in one person’s care.
55+ peer-reviewed studies. One patient's story. The evidence your doctor may not have found.
I recently, in the last year, suffered an injury that led to a diagnosis of Peyronie's disease — a condition that affects the penis. At first I was confused. I thought maybe I had an infection, but then the pain became unbearable. As it got worse I went to a specialist. The specialist had me meet his nurse first, who scheduled a meeting with him — three months out.
I finally met with him. He spoke to me for all of two minutes and scheduled a Doppler ultrasound. He said he anticipated we would need to use an injection to fix the issue, but he needed the Doppler first. However, they couldn't schedule the Doppler for three months.
I tried to set up the next appointment but was told it would be difficult to schedule the staff needed, and to put a tentative date three months out. They'd let me know if they could make it work.
88.4% of active-phase PD patients presenting to a specialist andrology clinic reported significant anxiety (GAD-7 >9, Paulis 2024 n=564 — note: 99.1% Caucasian, Italian single-center, specialist-seeking high-bother population; community rates and other demographics may differ)
Rates of depression vary by instrument and population: 27% on CES-D ≥16 (Punjani 2021, n=408); 47% as reported by Nelson and cited in CUA guidelines (Bella 2018 — instrument not specified in guideline text); 57.6% on PHQ-9 >9 in an active-phase specialist clinic (Paulis 2024, n=564). The range (27-58%) reflects different instruments, thresholds, and populations — not contradictory findings.
Depression is driven by bother and self-image, NOT by curvature degree — IIEF does not significantly correlate with curvature severity (p=0.359), plaque volume (p=0.09), or disease duration (p=0.554) (Paulis 2024, Table 7). This independently confirms Goldstein 2017's finding that improvement tracks with reduced bother, not mechanical correction.
Being partnered is protective against depression (OR 0.42, Punjani 2021)
56.4% of PD patients with ED had ED BEFORE developing PD (Paulis 2024) — ED is not always PD-caused. For patients whose ED partially predates PD, treating the PD alone may not fully resolve it.
Psychotherapy is clinically recommended:Paulis 2024 (n=564) concludes that "psychotherapy should be integrated into the treatment of PD patients to enhance quality of life and discourage them from discontinuing ongoing medical therapies." This isn't optional emotional support — it helps people stay on treatment. Patients may want to ask their urologist about a mental health referral.
Partners are affected too: 75% of female partners of men with PD met criteria for sexual dysfunction before treatment (Goldstein 2017)
This is the norm for PD patients, not a personal weakness. Treatment — even modest improvement — reduces bother and restores sense of agency, which drives quality-of-life improvement independently of curvature change. (See Evidence Reference §1.6)
Part 2 — Treatment Options
The Evidence Hierarchy — What Actually Works
The evidence hierarchy puts CCH and traction at the top. Verapamil has no controlled curvature evidence.
Tier 1: Strong controlled evidence
CCH (Xiaflex) — The only FDA-approved PD injection. Two large double-blind RCTs (IMPRESS, n=832) plus two meta-analyses confirm significant curvature improvement. (Detailed in Part 3A)
Tier 2: Positive controlled evidence, but guidelines oppose routine use
Hyaluronic Acid (HA) — Two double-blind RCTs show it outperforms verapamil. No significant or lasting adverse events reported. But ICSM 2024 (5th Consultation) recommends AGAINST routine HA use outside clinical trials, and EAU guidelines recommend against routine use. Approved only in Italy. (Detailed in Part 3B)
Tier 3: Supported by RCT, immediately actionable
RestoreX traction — RCT (n=100): -11.7° curvature improvement at just 30-90 min/day. Can start NOW — no prescription needed, no phase requirement. ICSM 2024 upgraded traction to Conditional Recommendation with Moderate Quality of Evidence — the most current major-society endorsement. (Detailed in Part 3C)
Tadalafil daily (5 mg) — Does NOT prevent curvature progression (Durukan 2024, P=.08). MAY shorten pain duration (9.1 vs 12.2 months, P=.04). Supports ED and penile oxygenation. Part of the Mayo Clinic oral protocol: pentoxifylline + L-citrulline + tadalafil. (See Evidence Reference §2.2)
Tier 5: No controlled curvature evidence
Verapamil injection — Two double-blind RCTs have tested verapamil head-to-head with HA, and verapamil was significantly inferior in both: Favilla 2017 (n=140, verapamil 0.00° ± 0.00 vs HA -4.60°, P<.001) and Abdel Fattah 2024 (n=42, verapamil -5.4° vs HA -9.4°, P=.038). No placebo-controlled trial has tested verapamil alone. Uncontrolled studies report improvement (e.g., Levine 2002, n=156: 60% "objectively improved") but lack placebo arms.
Plication, grafting, prosthesis — Gold standard for stable-phase PD with significant curvature. Plication does NOT cause additional length loss beyond what PD itself produces (Garaffa 2024, n=91, abstract only). Perception gap: Hudak found 84% had no measurable decrease in stretched penile length, but 78% perceived length reduction — the gap between measurement and perception is large and important for surgical counseling. Prior CCH does NOT increase surgical complications. Important expectations: Grafting curvature recurrence: 50-87% in longer-term follow-up (Osmonov ESSM 2022). Even with prosthesis, >25% of patients were dissatisfied with straightness despite achieving <20° residual curvature in the OR — "functionally straight" may not match patient expectations (Ziegelmann 2020). Note: surgical ED outcome data across most studies uses the IIEF questionnaire, which has not been validated for PD (Osmonov 2022) — ED rates are indicative, not precise. (See Evidence Reference §2.6)
Part 3A — CCH (Xiaflex): The Strongest Evidence
What it is: A bacterial enzyme that breaks down the collagen in PD plaques. The only FDA-approved injection for PD.
How well it works:
IMPRESS trials (n=832): 34% curvature improvement vs 18% placebo. The AUA guideline calls this "a modest difference of 7.7°" — honest framing (Gelbard 2013).
Pooled across 11 studies (n=1,480): 35% improvement with zero heterogeneity — remarkably consistent (Zhang 2022).
Less than half respond by strict criteria: In IMPRESS phase III, only 46% met the composite responder definition (≥20% curvature improvement + >1-point PDQ bother reduction). Flores 2022 (n=114, different metric): 44% improved, 39% no change, 17% worsened. Both measures converge: fewer than half of CCH patients achieve clinically meaningful improvement.
Important: These rates are from pre-selected favorable populations — IMPRESS excluded hourglass deformity, ED, ventral curvature, and significant calcification. Real-world patients are less pre-selected.
Real-world gap: Post-approval community data (Tsambarlis, per Ziegelmann 2020, n=45) found only 5.4° mean improvement vs IMPRESS's 17° — trial results don't always translate to community practice.
⊕ NEW: Trost-protocol outcomes (Cahill 2025, n=826): With aggressive modeling + 0.9mg dose + RestoreX, median improvement was 27.5-32.5° — nearly double IMPRESS. These are NOT standard CCH results — they require the specific Trost protocol. ⚠️ Triple COI: Trost is RestoreX inventor + PathRight part-owner + Endo-funded. Confound: 98% used RestoreX, insufficient non-use power to isolate its independent effect.
Predictors of CCH Response
Recent evidence has identified clinical factors that predict how a patient is likely to respond to CCH. These are general predictors that any PD patient and their urologist can apply to estimate likely benefit before starting treatment.
Curvature direction: Dorsal curvature shows the highest response rate — approximately 50% median improvement vs 33.6% for ventral curvature (Lumbiganon 2025, n=292). Lateral curvature is associated with 11° worse outcomes than dorsal in multivariate analysis (Cahill 2025, P<.001).
Baseline curvature degree: Greater baseline curvature predicts greater absolute improvement. Per 10° increase in baseline, the odds of clinically meaningful improvement increase (OR 1.33, Flores 2022). Cahill 2025 (n=826) found 0.5° greater curvature improvement per 1° increase in baseline curvature (P<.0001, multivariate).
Volume-loss / hourglass deformity: Counter to the historical assumption that hourglass deformity limits CCH candidacy, recent evidence shows the opposite. Cahill 2025 (n=826, multivariate P=.02) found that moderate or severe hourglass/indentation deformity predicts 3-10° MORE curvature improvement than absent or mild volume-loss. Patients with these features were excluded from the original IMPRESS trials, but real-world data suggests they may be among the best responders.
Part 3D — Verapamil
The evidence:
Two double-blind RCTs have tested verapamil head-to-head with HA. Verapamil was significantly inferior in both. Favilla 2017 (n=140): verapamil 0.00° ± 0.00 vs HA -4.60° (P<.001). Abdel Fattah 2024 (n=42): verapamil -5.4° vs HA -9.4° (P=.038). No placebo-controlled trial has tested verapamil alone.
Standard published protocols use weekly to biweekly intervals. Intervals beyond this have no published evidence base.
Why urologists sometimes choose verapamil: Cost ($60/year vs $15,000+ for CCH), availability, safety, and ability to use in acute phase. These are practical advantages. They don't overcome the absence of controlled curvature efficacy.
Guideline status: AUA says "may consider" (Conditional, Grade C) but calls the evidence "weak" and notes "the availability of other treatments that are clearly more effective." EAU recommends AGAINST (Level 4). CUA recommends (Level 3, Grade C — outlier, practice-based: "more than two decades of experience," not controlled evidence). ICSM: Conditional, "may reduce curvature in SOME patients." (See Evidence Reference §3D)
Part 4 — Decision Framework by Phase
The Phase Question
Treatment selection in PD depends primarily on disease phase: active (curvature still progressing) vs stable (curvature unchanged for ≥3 months). Each phase has different treatments with controlled evidence behind them.
The older clinical framing — that the "acute phase" lasts 12-18 months and patients should "wait and see" until then — has been abandoned. ICSM 2024 explicitly notes there is "no universally agreed-upon definition of the acute phase," and the field has shifted to defining phase by what the disease is doing, not by how long it has been doing it. A patient at 24 months whose curvature continues to worsen is in active phase; a patient at 6 months whose curvature has been stable for 3 of those months is in stable phase.
Phase classification ≠ surgical eligibility. Phase classification requires ≥3 months of stability. Surgical eligibility requires ≥6 months of stability per ICSM 2024 Recommendation #18 — a higher threshold. A patient who has just transitioned to stable phase is not yet a surgical candidate.
Treatment Options by Phase
This table summarizes which treatments have evidence for which phases. The cell descriptors are defined below.
Treatment
Active phase
Stable phase
Key evidence
CCH (Xiaflex)
Off-label viable
Recommended (FDA-approved)
IMPRESS RCTs (n=832): 34% improvement vs 18% placebo. Cocci 2020 (-19.3°, n=74) supports active phase. Cahill 2025 (P=.48, NS for phase).
Hyaluronic Acid (HA)
Positive evidence; guidelines oppose
Positive evidence; guidelines oppose
Favilla 2017 RCT (n=140): -4.6° vs verapamil 0.0° (P<.001). ICSM 2024 + EAU recommend against routine use outside trials.
RestoreX traction
Recommended
Recommended
Ziegelmann 2019 RCT (n=100): -11.7° at 30-90 min/day. ICSM 2024 Conditional Recommendation, Moderate Quality. No phase requirement.
Tadalafil daily
Reasonable adjunct
Reasonable adjunct
Does not prevent curvature progression (Durukan 2024, P=.08). May shorten pain duration. Mayo oral protocol component.
NSAIDs
Recommended for pain
Recommended for pain
All four major guidelines support for pain management. Does not address curvature.
Verapamil injection
No controlled curvature evidence
No controlled curvature evidence
Favilla 2017 RCT: zero curvature change. Guidelines split (AUA conditional, EAU against, CUA Grade C, ICSM conditional). See Part 3D for full breakdown.
Surgery
Not eligible
Eligible after ≥6 months stability
ICSM 2024 Rec #18: stable ≥6 months required. Plication, grafting, prosthesis depending on curvature degree and ED status.
Cell descriptor legend:
Recommended: Major guidelines support and there is controlled evidence in this phase.
Off-label viable: The treatment has clinical evidence in this phase, but the FDA label or formal guideline does not specify it. Some urologists offer it; insurance may resist.
Positive evidence; guidelines oppose: RCTs show benefit but major guidelines recommend against routine use outside clinical trials. Pursuing this means knowingly diverging from current guidelines.
Reasonable adjunct: Limited curvature evidence but reasonable to use alongside primary treatment for related symptoms (ED, pain, oxygenation).
Recommended for pain: Helps a specific symptom but does not address curvature.
No controlled curvature evidence: No controlled trial supports curvature benefit. Some guidelines may still permit use based on uncontrolled data; see the Key Evidence column for guideline positions.
Combination evidence (footnote):
CCH + RestoreX: Patients receiving both are 6.9× more likely to achieve ≥20° improvement than CCH alone (Alom 2019, abstract); 19.5° greater curvature improvement in multivariate analysis (Cahill 2025, P=.02). RestoreX was the strongest predictor of CCH response in Cahill 2025. Triple COI on the Trost protocol (Trost is RestoreX inventor + PathRight part-owner + Endo-funded); 98% RestoreX use in the cohort limits the ability to isolate its independent effect.
What it is: A bacterial enzyme injected directly into the PD plaque to break down its collagen. The only FDA-approved injection for PD.
Best evidence: IMPRESS Phase III double-blind RCTs (Gelbard 2013, n=832). Largest prospective predictor study: Cahill 2025 (n=826).
Typical outcomes: IMPRESS reported -17° absolute curvature improvement (-34%) vs placebo -9.3° (-18%, P<0.0001) — a difference the AUA characterizes as "a modest difference of 7.7°." Fewer than half of CCH patients achieve clinically meaningful improvement (46% IMPRESS composite responder; 44% improved in Flores 2022, n=114). Real-world community data: 5.4° mean improvement (Tsambarlis per Ziegelmann 2020, n=45) — substantially below trial outcomes.
Cahill 2025 modified-protocol outcomes: 27.5° median improvement (Most Recent definition) / 32.5° (Completed 8 cohort). ⚠️ Trost-modified protocol — NOT standard IMPRESS protocol (uses aggressive in-office modeling, 0.9 mg dose, wrapping, RestoreX in 98% of patients). The cohort's median baseline curvature was 65° — meaningfully higher than many patients will have. The 27.5° figure is anchored to that high-baseline cohort. NOT generalizable to community CCH practice.
Predictors of response (Cahill 2025 multivariate): dorsal direction (favorable); baseline curvature degree (0.5° more improvement per 1° baseline, P<.0001); moderate or severe hourglass / indentation deformity (3-10° MORE improvement, P=.02 — counter-intuitive vs historical assumption); calcification status NOT a reliable failure predictor (P=.37); concurrent RestoreX traction associated with 19.5° greater improvement (P=.02, the strongest predictor of all factors assessed); active phase NOT a barrier (P=.48 NS). Patient motivation/engagement also predictive: self-assessed decreased motivation = 7° less improvement (Cahill 2025, P<.01). Patient engagement requirement: CCH outcomes depend partly on active participation in modeling and traction adjuncts.
Limitations / caveats: 84.2% adverse event rate vs 36.3% placebo (IMPRESS, per AUA Nehra 2015); 0.36% penile fracture rate (3/832). Original IMPRESS trials excluded hourglass deformity, ED, ventral curvature, and significant calcification — pre-selected favorable population. COI on Cahill 2025 / Trost-modified protocol findings: Landon Trost is the inventor of RestoreX, part-owner of PathRight Medical, recipient of investigator-initiated grants from Endo Pharmaceuticals (CCH manufacturer), and Editor-in-Chief of J Sex Med (recused from this article's peer review per the published statement).
Cost / access: ~$15,000-18,000 total before insurance ($6,940-8,895/cycle, median 2 cycles per Walton 2022). Out-of-pocket <$300/cycle. US-only — withdrawn outside the United States.
Key findings: Largest PD cohort study. 74% mild-moderate curvature (≤60°). Independent predictors of curvature severity: age (P=.013), deformity side (P=.007), ED (P<.0001), diabetes (P=.001). ED was MORE common in milder deformity groups — proposed explanation: less intercourse → less cumulative trauma → less severe curvature. DM patients: mean curvature 45.2° vs 30.2° without DM. Dorsal curvature associated with more severe deformity (tunica thicker dorsally). Left-sided curvature 3× more frequent than right.
Limitations: Retrospective, single center, lacked obesity/smoking/testosterone data.
Key findings: 88.4% significant anxiety (GAD-7 >9). 38.8% severe anxiety. 57.6% significant depression (PHQ-9 >9). 24.2% were ≤40 years. 35.6% chronic prostatitis. 35.6% plaque calcification. 88.2% had penile shortening (most common deformity). 16.1% multifocal plaque. Active phase documented at 22-26 months in 5 patients — pain absent but curvature still worsening. Only 29% recalled specific penile trauma. ED pre-existed PD in 56.4% of PD+ED cases. Younger patients had more pain; older patients had more ED. IIEF did NOT correlate with curvature severity (p=0.359), plaque volume (p=0.09), or disease duration (p=0.554).
Limitations: 99.1% Caucasian, Italian single-center, specialist-seeking active-phase population only. Community rates likely differ. Referral bias elevates anxiety/depression rates.
ICSM 2024 (Chung 2026)
PMID: 41359447 | Design: Modified Delphi consensus | Journal: Sex Med Rev
Key finding on phases: "There is no universally agreed-upon definition of the acute phase, and there is likely heterogeneity in the timeline for most patients." Active phase = progressive deformity (functional definition), NOT fixed months. Stable phase = curvature unchanged ≥3 months. Surgical eligibility = stable ≥6 months. Pain may persist in stable phase ("pain with erection may be present due to torque or stretch on the penile scar"). Pain resolution alone does NOT confirm stability.
Also: IFN alpha-2B no longer commercially available. Traction: Conditional Recommendation (Moderate Quality of Evidence). SCT/PRP: Strong Recommendation against. CCH withdrawn outside USA.
Key findings: 67% stable, 21% worsen, 12% improve. Younger age (continuous predictor: per decade decrease, OR 2.1, P<.01) and ≤6 months from onset → better prognosis.
Grasso 2007 (abstract only)
PMID: 17601314 | Design: Observational | n: 110
Key findings: <50yr: 68% worsened and required surgery. ≥50yr: 31.5%. Diabetes OR=6 for progression.
Margolin 2018
PMID: 30342867 | Design: Retrospective | n: 128 | Journal: Sex Med
Key findings: 65% had volume-loss deformities (hourglass 23%, indentation 39%, distal tapering 13%). After controlling for curvature angle: axial instability OR 3.5 (P=.01), psychological distress OR 2.6 (P=.03), decreased sexual activity OR 2.7 (P=.02). Indentation: highest rates of instability (48%), distress (72%), decreased activity (62%).
Punjani 2021
PMID: 33712403 | Design: Retrospective | n: 408 | Journal: J Sex Med
Key findings: 27% clinically depressed (CES-D ≥16). Curvature degree NOT a predictor of depression on multivariable. Being partnered protective (OR 0.42, P<.01). Only total SEAR score significant on multivariable (OR 0.96, P<.001). Prior depression: OR 2.93.
Goldstein 2017
PMID: 28395998 | Design: Open-label phase 3 | n: 189 men + 30 partners | Journal: Sex Med
Key findings: 36.3% curvature improvement. Female partner sexual dysfunction dropped 75% → 33.3%. BUT: correlation between curvature improvement and partner FSFI improvement was LOW and NOT significant — partner benefit appears driven by reduced bother/behavioral change, not curvature correction.
Mulhall 2019
PMID: 31303573 | Design: Prospective database | n: 184 | Journal: J Sex Med
Key findings: Total testosterone NOT associated with curvature magnitude (r=-0.01, P=0.95). Free testosterone NOT associated (r=-0.08, P=0.30). No association in multivariable model. Critiques Moreno study methodology.
Chierigo 2026 (Guideline of Guidelines)
PMID: 41795618 | Design: Guideline synthesis | Journal: BJU Int
Key finding: Cross-society comparison of AUA/EAU/CUA/ISSM. Significant divergences on verapamil (AUA conditional, CUA recommends, EAU against), CCH (EAU strongest endorsement at Level 1b), HA (EAU/ICSM against outside trials). North American guidelines more permissive than EAU.
⊕ Correction: Chierigo rendered CUA's verapamil position as Level 2, Grade B. Primary source (Bella 2018) shows Level 3, Grade C. GoG overstated CUA's evidence grading.
Key findings: Verapamil: "Conditional Recommendation, Grade C" — "the evidence for the use of intralesional verapamil is weak; clinicians should carefully consider whether use of this treatment is appropriate given the substantial uncertainty regarding its efficacy and the availability of other treatments that are clearly more effective." CCH: "Moderate Recommendation, Grade B" — "a modest difference of 7.7°." ESWT: "overall utility of ESWT in the management of PD is low." Traction: "insufficient evidence" (Other Treatments table). IFN: "most appropriate for the patient with stable disease."
Key findings: Only major society that RECOMMENDS intralesional verapamil (Level 3, Grade C) — "widely used in Canada with more than two decades of experience." Recommends traction (Level 4, Grade C). HA: "too early to make any recommendations." ⊕ Internal inconsistency: cites Favilla 2017 (ref 52) for HA evidence but does NOT reconcile the zero verapamil finding with ongoing verapamil recommendation. Plication perception gap (Hudak): 84% no measurable SPL decrease, 78% perceived reduction.
Key findings: 21% currently use AUA-discouraged treatments. Only 60% perform in-office curvature assessment. 81% have NO fellowship training in andrology/sexual medicine. Fellowship-trained vs non-fellowship: CCH 89% vs 54% (P<.001), traction 78% vs 47% (P=.004), in-office assessment 85% vs 54% (P=.003), duplex US 70% vs 24% (P<.001). 41% of CCH users use it off-label. Even among those claiming to follow AUA guidelines, 21% still use discouraged treatments. Younger urologists (<20 years) more evidence-based across most measures (in-office assessment, duplex US, validated questionnaire, AUA Algorithm); the AUA-discouraged-treatment use was qualitatively higher in the younger group (25% vs 17%, NS). Self-selection bias: 21% AUA-violation figure likely underestimates real-world non-adherence.
Key findings: 35% pooled curvature improvement (I²=0.00% — zero heterogeneity). 41% PD bother improvement. 93% TRAEs (mostly mild). Modified protocols may retain same effectiveness. No publication bias for curvature outcome.
Gelbard 2013 — IMPRESS I+II (abstract only for primary, cited in multiple sources)
Key findings: CCH -17° (-34%) vs placebo -9.3° (-18%), P<0.0001. AUA characterizes the net difference as "a modest difference of 7.7°." 46% met composite responder criteria (≥20% curvature improvement + >1-point PDQ bother reduction). 3 corporal ruptures (0.36%). 84.2% of CCH patients had ≥1 adverse event vs 36.3% placebo. A separate Phase IIb study (Gelbard 2012, Levine 2012 — outside the IMPRESS Phase III publication) reported no significant benefit in the non-modeling arm; the citation chain for this claim is via secondary review rather than the primary IMPRESS Phase III paper. Modeling contributes substantially to outcomes. Exclusions: hourglass, ED, ventral curvature, significant calcification — pre-selected favorable population.
Flores 2022
PMID: 36127227 | Design: Retrospective | n: 114 | Journal: J Sex Med
Key findings: 44% improved, 39% no change, 17% worsened (improvement threshold has internal inconsistency: abstract says ≥20%, Table 2 footnote says ≥25%). Among responders: mean -22° (-41%). Baseline curvature THE predictor: OR 1.33 per 10° (P=.02). By baseline: ≤30°: 29%, 31-59°: 43%, ≥60°: 60%. Calcification NS (OR 0.92, P=.88 — likely underpowered, ~15% calcified). Cycle-2 decision principle supported. Traction 2-6h/day.
Lumbiganon 2025
PMID: 40223660 | Design: Retrospective 7-year | n: 292 | Journal: J Sex Med
Key findings: 70.89% compliance. Compliant: 44.44% curvature reduction vs non-compliant 33.33% (P=.034). Dorsal among the best response categories (50.09%); ventrolateral comparable (50.72%) and multiple-curvature highest (~56%); ventral worst (33.57%). 4 suspected penile fractures (1.4%) reported during the study period in patients on standardized 3×/day modeling. Non-compliance: AEs 15.1%, early satisfaction 14.1%, unknown 45.4%.
PMID: 35252236 | Design: Meta-analysis, 5 RCTs | n: 1,227 | Journal: Front Med
Key findings: CCH significant for curvature (P<0.001) and bother (P<0.001). Pain: NO difference vs placebo (P=0.39). TAE OR 12.86 (P<0.001). No industry funding.
Limitations: Only 5 RCTs available for inclusion (industry funding history of CCH program is documented in the underlying IMPRESS publications, not in this meta-analysis).
Key findings: Single CCH injection in acute phase: -19.3° (P<0.0001). Baseline curvature and time since onset predicted improvement. Off-label for acute phase. Uncontrolled.
Trost 2021
PMID: 33684795 | Design: Claims database, PS-matched | n: 620/cohort | Journal: Sex Med
Key findings: CCH fewer post-procedural complications (18.4% vs surgery 25.3%, P=.003). Less ED (44.8% vs 65.0%). Less opioid use (38.9% vs 93.3%). Corporal rupture: CCH 1.8% vs surgery 0.8% (NS).
Limitations: Claims-based — no clinical curvature measurements. Endo Pharmaceuticals-funded.
Trost 2023
PMID: 35013566 | Design: Claims database | n: 1,227+620 | Journal: Int J Impot Res
Key findings: CCH first → 4.6% subsequent surgery (12 months) vs surgery first → 10.3% (P<0.0001). Difference narrowed at 24 months (8.7% vs 10.7%, NS). Prior CCH does NOT increase surgical complications.
Key findings: Noncalcified patients OR 2.50 for CCH improvement. 67% noncalcified vs 41% calcified improved.
Masterson 2023 (abstract only)
PMID: 36272924 | Design: Prospective (per PubMed abstract; primary article not on disk) | n: 47
Key findings: Calcified patients CAN improve with CCH (-17.5°). Contradicts Wymer — needs reconciliation.
Calcification evidence status (updated with Cahill 2025): Three data points — one positive (Wymer, n=115), one contradictory (Masterson, n=47), one NS in the largest series (Cahill, n=826, P=.37). Weight of evidence now favors: calcification is NOT a reliable predictor of CCH failure. Partial calcification is not a contraindication. ICSM 2024: "calcification does not signify chronic disease — may represent a different genetic subtype." See consolidated Cahill 2025 entry below.
Walton 2022
PMID: 35461065 | Design: Claims database | n: 89,205 | Journal: Sex Med
Key findings: CCH $6,940-8,895/cycle, median 2 cycles = ~$15-18K total. OOP <$300/cycle. Surgery $1,856-3,631. Verapamil ~$60/year.
Cahill 2025 — LARGEST PROSPECTIVE CCH PREDICTOR STUDY
PMID: 40814201 | Design: Prospective sequential database | n: 826 | Journal: J Sex Med 2025
Key findings:
Median curvature improvement: 27.5° (Most Recent) / 32.5° (Completed 8 or Satisfied). ⚠️ Trost-protocol specific — uses aggressive in-office modeling, 0.9mg dose, wrapping, and RestoreX in 98% of patients. NOT standard IMPRESS protocol. Not generalizable to community CCH practice.
RestoreX: Associated with 19.5° greater improvement on multivariate (P=.02). The strongest predictor across all models. ⚠️ Confound: By 2019+, 98% used RestoreX → insufficient power in non-use arm → cannot cleanly separate RestoreX benefit from concurrent protocol changes.
Hourglass/indentation: Moderate/severe → 3-10° MORE improvement than none/mild (P<.0001 univariate; multivariate P=.02). Counterintuitive: More severe indentation predicts BETTER CCH response. Contradicts prior assumption that hourglass precludes CCH.
Calcification: NS (P=.37) — not a significant predictor. See calcification evidence status above (Wymer/Masterson/Cahill synthesis).
Active phase: NS (P=.48) — CCH may safely and effectively be used in active phase.
Disease duration: NS (P=.37) — duration does not predict outcomes.
Lateral curvature: -11.2° worse outcomes (multivariate P<.001). Dorsal/dorsolateral: best response.
Motivation/bother: Higher PDQ bother and psych/physical scores correlated with better outcomes. Decreased self-reported motivation: 7° worse.
IIEF: Zero change post-CCH across all domains (consistent with Osmonov: IIEF not validated for PD).
44% completed 4 series or stopped satisfied — consistent with Flores 44%.
Limitations: Single-center (Trost's clinic, Utah). Protocol evolved substantially over 10 years. RestoreX confound. ⚠️ Triple COI: Trost is inventor of RestoreX, part-owner of PathRight Medical, and received investigator-initiated grants from Endo Pharmaceuticals (CCH manufacturer). Also Editor-in-Chief of J Sex Med (the publishing journal). Declared; editorial process delegated.
Key findings: Verapamil: 0.00° ± 0.00 curvature change. HA: -4.60° (P<0.001). Both reduced plaque (-1.36mm vs -1.80mm, NS). Both improved IIEF (NS between groups). HA PGI-I: 3.13 vs V 3.53 (P<0.05). No injection-site ecchymosis, hematomas, or other significant adverse events reported. Acute phase, 11 Italian centers, weekly × 12 weeks.
Key findings: Only HA study in stable phase. 3 injections at 2-week intervals + vacuum + stretching + modeling. 87.1% responded. Mean -12.4° (23%). Calcification NOT predictive (P=0.847). No long-lasting local adverse effects reported. Cannot separate HA effect from mechanical adjunct.
Ziegelmann 2019 RestoreX RCT (abstract; full data in Ziegelmann 2020 review)
PMID: 30916626 | Design: RCT | n: 100
Key findings: RestoreX 30-90 min/day × 3 months. Curvature: -11.7° vs +1.3° control (ITT). SPL: +1.5cm vs 0cm. >75% curvature improvement; ~95% SPL improvement. First study showing benefit at <3 hours daily. Note: Ziegelmann is both the RCT author and the 2020 review author (self-citation).
Key findings: Best combo (Group 2: verapamil injection + iontophoresis + vit E + diclofenac + propolis): -14°. Group 3 (verapamil injection + vit E + topical diclofenac, no iontophoresis or propolis): -2.7°. Group 4 (verapamil iontophoresis + vit E + topical diclofenac, no injection): -4.5°. None of the arms tested verapamil monotherapy. Active ingredient may be propolis (NF-κB inhibitor), not verapamil.
Levine 2002
PMID: 12454681 | Design: Uncontrolled | n: 156
Key findings: 60% "objectively improved." No placebo. 30.4 months follow-up. The foundational verapamil paper. Stub — limited content.
Osmonov 2022 (ESSM Position Statement)
PMID: 34823053 | Design: Systematic review, 131 studies | Journal: Sex Med
Key findings: 18 position statements. Plication: straightening 48-100%, satisfaction 58-96%. Grafting: recurrence 50-87% long-term. TachoSil: 83-95% straightening, 91.5% satisfaction, shortest operative time. Glans hypoesthesia: plication up to 53%, grafting up to 39% — mostly transient. Statement #14: post-CCH surgery feasible without increased complications (harder within 3 months). >70% of patients report penile shortening BEFORE surgery. IIEF not validated for PD — all surgical ED outcome data uses a non-validated instrument.
Limitations: Literature 2009-2019 only. Misses RestoreX RCT and all post-2019 data.
Garaffa 2024 (abstract only)
PMID: 38388784 | n: 91
Key finding: Plication does NOT cause additional length loss (P=0.466). "The perceived length loss has already occurred prior to surgery." Perception gap (Hudak): 84% no measurable loss, 78% perceived loss.
Key findings: Extra-tunical grafting (ETG) for hourglass/indentation. All 17 reported satisfactory resolution — but 13/17 had concurrent plication. 94.1% satisfied, 11.8% mild hypoesthesia, zero ED worsening. ETG does NOT violate tunica albuginea or dissect NVB. Also used for post-CCH corporeal herniation. Graft initially more prominent in flaccid state, normalizes by 6 months.
Limitations: n=17, retrospective, single surgeon, no validated questionnaire, plication confound in 76% of cohort. Promising preliminary evidence, not established efficacy.
