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Management of Peyronie's Disease and Erectile Dysfunction

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PEYRONIE'S DISEASE (PD)

Overview

Pathogenesis

Disease Phases

Diagnosis

• History: sexual history, onset, pain, curvature direction, penetrative difficulty, psychosocial impact
• Examination: palpable tunical plaque; check hands/feet for Dupuytren's contracture (co-occurs in ~21%) or Ledderhose disease
• Objective assessment: stretched penile length, plaque size; erect photography (natural, VED-assisted, or post-ICI)
• Imaging: Doppler duplex ultrasound — highest sensitivity for calcified and soft-tissue plaques; assesses arterial/venous status simultaneously

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Treatment of PD: A Phase-Based Approach

1. Conservative / Observation

2. Medical (Non-surgical) Treatment — Acute/Active Phase

Oral Therapies

Most oral agents have failed to demonstrate significant benefit in well-designed RCTs. Pentoxifylline within a multimodal strategy remains the recommended oral component.

Intralesional Injection (ILI) Therapy — First-Line Interventional

Physical/Device-Based Therapies (Adjunct)

• Penile traction therapy (PTT): Used alongside ILI; helps maintain/restore penile length, may reduce curvature — especially in the acute phase
• Vacuum erection device (VED): Adjunct to help preserve length and aid in monitoring curvature
• Extracorporeal shockwave therapy (ESWT): May reduce pain but does NOT reduce curvature — not recommended for deformity correction
• Topical therapies / iontophoresis / radiation therapy: Not currently recommended by AUA or EAU guidelines

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3. Surgical Treatment — Stable/Chronic Phase Only

• Deformity impairing sexual function
• Stable disease
• Extensive plaque calcification
• Failed minimally invasive treatment
• Desire for rapid, reliable correction

When PD coexists with significant ED unresponsive to medications, penile prosthesis implantation is the preferred surgical option, as it addresses both conditions simultaneously. Intraoperative modeling can correct residual curvature at the time of IPP placement.

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ERECTILE DYSFUNCTION (ED)

Definition & Epidemiology

Pathophysiology

• Vascular (most common): atherosclerosis, hypertension, diabetes, hyperlipidemia
• Neurogenic: spinal cord injury, radical prostatectomy, pelvic radiation, diabetes, MS
• Hormonal: hypogonadism, hyperprolactinemia, thyroid disease
• Psychogenic: performance anxiety, depression, relationship dysfunction
• Drug-induced: antihypertensives (especially thiazides, non-selective β-blockers), antidepressants (SSRIs), antipsychotics, antiandrogens (~25% of ED cases are medication-related)

ED may precede symptomatic cardiovascular disease — men presenting with ED should receive a cardiac risk assessment (Princeton Consensus guidelines).

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Management of ED

Step 1 — Initial Evaluation

• SHIM (Sexual Health Inventory for Men) or IIEF questionnaire
• Full history: risk factors, medications, psychosocial, libido, partner relationship
• Examination: genitalia, secondary sexual characteristics, vascular, neurological
• Labs: FPG/HbA1c, lipids, renal function, urinalysis, total testosterone (morning). Add free T, LH, prolactin if signs of hypogonadism or low total T.

Step 2 — Address Reversible Causes

• Lifestyle modification: weight loss (improves erectile function in obese men), exercise, smoking cessation, alcohol reduction
• Medication review: substitute offending drugs where possible (e.g., switch from non-selective β-blocker to nebivolol; switch from SSRI to bupropion for antidepressant-induced ED)
• Treat underlying conditions: optimize glycemic control, treat hypogonadism (testosterone replacement restores libido and often improves erectile response)

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Step 3 — Pharmacological Treatment

First-Line: PDE5 Inhibitors

• Absolute CI: concurrent nitrate use (risk of severe hypotension; minimum 6-hour interval required between a nitrate dose and a PDE5i; for tadalafil some sources suggest 24–48 hours given its longer half-life)
• Caution with α-blockers (orthostatic hypotension); use lowest dose; avoid in recent stroke/MI
• PDE5is are ineffective in men with complete loss of nerve supply (e.g., bilateral cavernous nerve injury after RP) or absent libido — they require intact NO pathway

• Diabetes/ED: PDE5is are effective but may require higher doses; success rate ~50–70%
• Post-radical prostatectomy: early penile rehabilitation with PDE5is (daily or on-demand) may improve recovery; ICI is often needed
• Antidepressant-induced ED: add PDE5i, switch to bupropion, or consider drug holiday
• Spinal cord injury: PDE5is can be effective with preserved reflex erections

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Second-Line: Intracavernosal/Intraurethral Therapy

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Mechanical Devices

• Vacuum Erection Device (VED): Negative pressure draws blood into corpora; tension ring maintains erection. Effective, non-invasive; often useful in post-prostatectomy rehabilitation. Main drawback: "cold, pivot-point" erection; less spontaneous.

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Third-Line: Surgical — Penile Prosthesis Implantation

• Inflatable Penile Prosthesis (IPP): 2-piece or 3-piece; gold standard for refractory ED; high satisfaction rates (>90% patient and partner)
• Semi-rigid (malleable) prosthesis: simpler, fewer mechanical failures; less "natural" appearance

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Special Consideration: PD + ED — Integrated Management

1. Assess which is the primary complaint — curvature vs. erectile rigidity
2. If mild–moderate ED + active PD: pentoxifylline + PDE5i + ILI (CCH or verapamil) ± traction
3. If moderate–severe ED + stable PD: penile prosthesis implantation is the preferred surgical option — IPP corrects rigidity; residual curvature is managed intraoperatively via manual modeling or adjunct plication
4. Psychosexual counseling at all stages — PD+ED combined carries significant psychological burden

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Summary Algorithm

ED Diagnosis
    │
    ├─ Lifestyle modification + treat reversible causes (all patients)
    │
    ├─ 1st Line: PDE5 inhibitor (all neurologically/hormonally intact patients)
    │       └─ Testosterone deficiency? → Testosterone replacement FIRST
    │
    ├─ 2nd Line: VED, ICI (alprostadil ± papaverine ± phentolamine), MUSE
    │
    └─ 3rd Line: Penile prosthesis implantation

PD Diagnosis
    │
    ├─ Acute phase: Pentoxifylline + ILI (CCH/verapamil) + traction ± PDE5i
    │
    ├─ Stable phase + adequate erectile function: ILI (CCH) ± plication surgery
    │
    └─ Stable phase + significant ED: Penile prosthesis implantation ± intraoperative modeling

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• Smith and Tanagho's General Urology, 19th Ed. — Peyronie's Disease, pp. 638–639
• Campbell-Walsh-Wein Urology — Etiology, ED in PD, Psychological Aspects, pp. 2130–2134
• Goodman & Gilman's Pharmacological Basis of Therapeutics — PDE5 Inhibitors, p. 1018
• Katzung's Basic and Clinical Pharmacology, 16th Ed. — Drugs for ED, p. 309
• Textbook of Family Medicine, 9th Ed. — Erectile Dysfunction, p. 1193–1194
• AUA Peyronie's Disease Guideline — CCH for stable PD with curvature 30°–90°
• AUA Erectile Dysfunction Guideline (2018)
• ICSM 2024 PD Recommendations (PMID: 41359447) — most recent international consensus

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Akathisia — Causes, Drugs, and Management

Definition

• Subjective: overwhelming inner restlessness, dysphoria, mental unease, sense of terror ("inner akathisia" when purely subjective)
• Objective: inability to stay still; characteristic movements — rocking foot to foot, marching/walking in place, pacing, crossing/uncrossing legs, trunk rocking, fidgeting
• Frequently misdiagnosed as anxiety, mania, agitation, panic disorder, ADHD, or restless legs syndrome
• Associated with suicidal ideation — a clinically important risk

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Subtypes

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Pathophysiology

1. Dopaminergic: Blockade or depletion of D2 receptors, particularly in the mesocortical pathway (VTA → limbic system and prefrontal cortex) → reduced inhibitory control over motor activity. PET studies show correlation between D1/D2 binding in the putamen and akathisia.
2. Serotonergic: SSRIs cause akathisia possibly via 5-HT2C receptor effects indirectly suppressing dopaminergic activity; also relevant to 5-HT2A involvement.
3. Noradrenergic: Changes in noradrenaline levels affect dopamine indirectly (explains why β-blockers are therapeutic).
4. For withdrawal akathisia: abrupt reduction in dopaminergic or GABAergic tone → rebound motor dysregulation.

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CAUSES AND CAUSATIVE DRUGS

1. Antipsychotics (Dopamine D2 Receptor Antagonists) — Most Common Cause

First-Generation (Typical) Antipsychotics — HIGH risk

Second-Generation (Atypical) Antipsychotics — variable risk

A 2023 dose-response meta-analysis (Maudsley Prescribing Guidelines, 15th ed.) confirmed that risk generally increases with dose, but plateau behavior varies by agent.

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2. Antiemetics / Prokinetics — Important Non-Psychiatric Cause

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3. Antidepressants

SSRIs can cause acute akathisia AND withdrawal akathisia on discontinuation. Paroxetine (short half-life, strong serotonergic/anticholinergic) has the highest withdrawal akathisia risk among SSRIs.

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4. Antidepressant / Antipsychotic Withdrawal

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5. VMAT2 Inhibitors (used for hyperkinetic disorders)

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6. Calcium Channel Blockers

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7. Other Drug Classes

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8. Non-Drug Causes

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Risk Factors for Developing Akathisia

• Higher antipsychotic dose
• Antipsychotic polypharmacy
• Rapid dose titration
• High-potency D2-blocking agents
• Parenteral (IV/IM) administration
• Middle-aged women (higher risk)
• Pre-existing parkinsonian symptoms
• Prior akathisia episodes

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Differential Diagnosis

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Treatment

• Reduce antipsychotic dose to minimum effective
• Switch to an antipsychotic with lower akathisia liability (e.g., quetiapine, clozapine, brexpiprazole)
• Avoid antipsychotic polypharmacy and rapid dose increases

Anticholinergics alone are not particularly effective for akathisia (unlike for acute dystonia or parkinsonism). They are more useful when akathisia coexists with drug-induced parkinsonism.

Withdrawal akathisia (from benzodiazepines, SSRIs, antipsychotics) can be treated by cautiously reinstituting the withdrawn drug and tapering more slowly; standard akathisia medications have limited evidence in this specific subtype.

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Clinical Pearls

• Akathisia is commonly overlooked or misdiagnosed — clinical awareness is critical
• The Barnes Akathisia Rating Scale (BARS) is the standard validated tool for assessment
• Association with suicidality is clinically important — always ask about suicidal ideation when akathisia is suspected
• Akathisia does not correlate with objective restlessness severity alone — subjective distress must be assessed
• Evaluate each treatment option for at least 1 month before switching; withdraw ineffective treatments before starting the next

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• Maudsley Prescribing Guidelines in Psychiatry, 15th Ed. — Akathisia, p. 156–157
• Maudsley Deprescribing Guidelines — Withdrawal Akathisia (antidepressant & benzodiazepine withdrawal), pp. 201, 563
• Stahl's Essential Psychopharmacology — D2 blocker EPS, p. 185
• Adams and Victor's Principles of Neurology, 12th Ed. — Akathisia, p. 116
• Localization in Clinical Neurology, 8th Ed. — Drug-induced akathisia, p. 1115
• Kaplan & Sadock's Synopsis of Psychiatry — Medication-Induced Acute Akathisia, p. 1792
• RACGP: Beyond Anxiety and Agitation — A Clinical Approach to Akathisia
• Carlat Report 2024: meta-analyses supporting propranolol and mirtazapine as best-evidence treatments

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Management of Severe and Tardive Akathisia

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Key Preliminary Points

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Assessment

Validated Scales

• Barnes Akathisia Rating Scale (BARS) — gold standard; assesses objective restlessness, subjective awareness, and subjective distress
• AIMS (Abnormal Involuntary Movement Scale) — used when tardive dyskinesia coexists

Severity Classification (BARS Global Score)

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MANAGEMENT OF SEVERE AKATHISIA

Step 1 — Modify the Causative Drug (Immediate)

For antiemetic-induced severe akathisia (e.g., IV metoclopramide): stop the agent immediately. Parenteral midazolam (1.5 mg) has been shown effective for prophylaxis and rescue in this context.

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Step 2 — Pharmacological Add-On Treatment

First-Line Options

Note: Although benzodiazepines ranked highest by P-score in the Gambolò NMA (P-score 0.8186), the JAMA NMA did not find clonazepam statistically superior to placebo in head-to-head RCTs — their benefit may be via nonspecific anxiolytic/sedative effects. They remain useful for rapid symptom relief in severe/acute presentations.

Effective Alternatives

Not Recommended (Ineffective in RCT/NMA)

• Valproate — not significant in NMA
• Zolmitriptan — not significant in NMA
• Anticholinergics alone without parkinsonism — limited benefit for pure akathisia

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Step 3 — Refractory Severe Akathisia

Evaluate each treatment for at least 1 month before declaring failure. Withdraw ineffective agents before adding the next. Combinations may be considered with careful monitoring.

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MANAGEMENT OF TARDIVE AKATHISIA

Step 1 — Careful Antipsychotic Modification

Per the 2025 WFSBP/INTEGRATE International Guidelines: for tardive syndromes, switching to clozapine, olanzapine, quetiapine, or a D2 partial agonist should be discussed. VMAT2 inhibitors are the next step.

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Step 2 — VMAT2 Inhibitors (Key Treatment for Tardive Syndromes)

If one VMAT2 inhibitor fails or is intolerable, switch to the other before abandoning the class. Sedation, drug-induced parkinsonism, and akathisia from VMAT2 inhibitors are managed by dose reduction.

Anticholinergics are contraindicated for tardive syndromes — they do not help and may worsen tardive dyskinesia.

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Step 3 — Additional Pharmacological Options for Tardive Akathisia

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Step 4 — Refractory Tardive Akathisia

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Management of Withdrawal Akathisia

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Summary Algorithm

SEVERE AKATHISIA
├── IMMEDIATE: Reduce/switch offending drug
│       ├── Reduce dose 25–50%
│       └── Switch to quetiapine / clozapine / brexpiprazole
│
├── ADD PHARMACOTHERAPY (choose based on comorbidities):
│       ├── Mirtazapine 15 mg/d  [most efficacious per 2024 JAMA NMA]
│       ├── Vitamin B6 600–1200 mg/d  [best efficacy/tolerability]
│       ├── Biperiden 6 mg/d  [if parkinsonism coexists]
│       ├── Propranolol 30–120 mg/d  [first-line in many guidelines]
│       ├── Trazodone 50 mg/d or Mianserin 15 mg/d
│       └── Benzodiazepine (clonazepam/lorazepam) for urgent relief
│
└── REFRACTORY: Combine agents + consider clozapine

TARDIVE AKATHISIA
├── Step 1: Slow/gradual dose reduction OR switch to clozapine/quetiapine
│
├── Step 2: VMAT2 Inhibitor (AAN Level A)
│       ├── Valbenazine 80 mg/day  [once daily; preferred]
│       └── Deutetrabenazine 12–48 mg/day  [twice daily; individualized]
│
├── Step 3: Adjuncts — clonazepam, propranolol, mirtazapine, amantadine
│
└── Refractory: Clozapine + VMAT2 inhibitor combination

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• Maudsley Prescribing Guidelines in Psychiatry, 15th Ed. — Akathisia Treatment Algorithm, pp. 156–157
• Maudsley Deprescribing Guidelines — Withdrawal Akathisia, pp. 563, 637
• Gerolymos C et al. Drug Efficacy in Treatment of AIA: Network Meta-Analysis. JAMA Netw Open 2024 — mirtazapine #1, biperiden #2, vitamin B6 #3
• Gambolò L et al. Comparative efficacy of akathisia treatments: Network meta-analysis. CNS Spectr 2024 — benzodiazepines, β-blockers, NaSSA confirmed effective
• Vanegas-Arroyave N et al. Anticholinergic Use for Drug-Induced Movement Disorders. CNS Drugs 2024
• 2025 WFSBP/INTEGRATE International Guidelines for Schizophrenia — VMAT2 inhibitors for tardive syndromes; propranolol/mirtazapine for akathisia
• AAN Level A evidence: valbenazine and deutetrabenazine for tardive dyskinesia/syndrome