What is the differential diagnosis (Dx) for a tingling sensation with episodic pain on the penile or urethral tip?

Differential Diagnosis for Tingling Sensation with Episodic Pain on Penile/Urethral Tip

The most likely diagnoses are urethritis (infectious or non-infectious), chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), and urethral pain syndrome, with urethritis being most probable if this is the only symptom. 1

Primary Differential Diagnoses

Urethritis

• Infectious urethritis is the leading consideration in sexually active men, caused primarily by Chlamydia trachomatis or Neisseria gonorrhoeae in men under 35 years. 2, 3
• Symptoms typically include penile itching or tingling and dysuria, though discharge may be absent in some cases. 3
• Diagnosis requires at least one of: urethral discharge, positive leukocyte esterase test in first-void urine, or ≥10 white blood cells per high-power field in urine sediment. 3
• Obtain a Gram-stained smear of urethral exudate (>5 polymorphonuclear leukocytes per oil immersion field indicates urethritis) and nucleic acid amplification test on intraurethral swab or first-void urine for N. gonorrhoeae and C. trachomatis. 2, 1

Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS)

• CP/CPPS should be strongly considered when pain at the penile tip persists for ≥3 months, particularly if exacerbated by urination or ejaculation. 1
• Pain is characteristically localized to the perineum, suprapubic region, testicles, or tip of the penis, and patients often describe "pressure" rather than pain. 1
• Associated symptoms include sense of incomplete bladder emptying, nocturia, and urinary urgency (though urgency is driven by desire to relieve pain rather than true bladder fullness). 1
• This diagnosis requires exclusion of infection through urinalysis and urine culture. 1

Urethral Pain Syndrome

• Characterized by persistent or recurrent episodic urethral pain (usually on voiding) with daytime frequency and nocturia, in the absence of proven infection. 4, 5
• More common in women but does occur in men. 5
• Symptoms overlap significantly with interstitial cystitis/bladder pain syndrome and overactive bladder. 5
• Diagnosis is primarily symptom-based after excluding other lower urinary tract pathology. 4, 5

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)

• Should be strongly considered in men whose pain is perceived to be bladder-related, as clinical characteristics overlap significantly with CP/CPPS. 1
• Some men meet criteria for both CP/CPPS and IC/BPS and may require combined treatment approaches. 1

Secondary Differential Diagnoses

Lichen Sclerosus with Penile Dysaesthesia

• Men may develop abnormal burning sensation on the glans or around the urethral meatus despite clinical improvement or resolution of visible skin lesions. 2
• This represents neuropathic pain that does not respond to topical corticosteroids. 2
• Look for associated findings of lichen sclerosus: white plaques, phimosis, or meatal stenosis. 2

Epididymitis

• Less likely if pain is isolated to the penile/urethral tip without testicular involvement. 2, 6
• Typically presents with unilateral testicular pain and tenderness, hydrocele, and palpable epididymal swelling. 2, 6
• In sexually active men <35 years, most often caused by *C. trachomatis* or *N. gonorrhoeae*; in men >35 years or after urinary instrumentation, consider enteric organisms. 2

Penile Neuropathy

• Consider in patients with diabetes or history of trauma, toxin exposure, or nerve compression. 7
• Presents with sensory signs (hypoesthesia or paresthesia of the penis) and may include sexual dysfunction. 7
• Electrophysiological recordings showing reduced sensory velocity of the dorsal nerve of the penis can confirm diagnosis. 7

Essential Diagnostic Workup

Initial Laboratory Testing

• Urinalysis and urine culture are basic requirements. 1
• First-void urine for leukocyte esterase test and microscopy. 3
• Gram-stained smear of urethral exudate or intraurethral swab. 2, 1
• Nucleic acid amplification test for N. gonorrhoeae and C. trachomatis on intraurethral swab or first-void urine. 2, 1
• Consider testing for atypical organisms (Mycoplasma genitalium, Ureaplasma species) if initial tests are negative. 3

Additional Considerations

• Syphilis serology and HIV testing should be offered to all patients diagnosed with urethritis. 2
• If symptoms persist >3 months without evidence of infection, consider CP/CPPS or urethral pain syndrome. 1, 4

Critical Pitfalls to Avoid

• Do not dismiss patients who describe "pressure" rather than "pain"—this is common in CP/CPPS and IC/BPS. 1
• Recognize that CP/CPPS and IC/BPS have overlapping presentations; some patients meet criteria for both conditions and require combined treatment approaches. 1
• Do not assume absence of urethral discharge excludes urethritis—many cases present with only dysuria and penile tingling. 3
• Neuropathic pain from lichen sclerosus will not respond to topical corticosteroids; treatment must target neuronal sensitization. 2
• If treating empirically for urethritis without improvement after 3 days, reevaluate both diagnosis and therapy. 2

Empiric Treatment Approach (When Urethritis is Suspected)

• First-line therapy: Azithromycin 1 g orally single dose OR doxycycline 100 mg orally twice daily for 7 days. 2
• For suspected gonococcal infection: Add ceftriaxone 250 mg IM single dose. 2, 3
• Instruct patient to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of 7-day regimen. 2
• All sex partners within preceding 60 days should be treated empirically. 2