What is the optimal pain management and antibiotic regimen for syphilis, including primary chancre pain, treatment options for pregnancy or penicillin allergy, and neurosyphilis?

Pain Management and Treatment of Syphilis

Pain Management for Primary Chancre

Primary syphilitic chancres are characteristically painless and do not require specific analgesic therapy. 1, 2, 3 The painless nature of the primary chancre is a defining clinical feature that distinguishes syphilis from other causes of genital ulceration such as herpes simplex virus. 2, 3

• If a patient presents with a painful genital ulcer after recent syphilis treatment, do not assume treatment failure—instead evaluate for herpes simplex virus, trauma, or reinfection with appropriate testing including HIV screening if not already performed. 4
• True syphilis treatment failure is defined serologically (failure of nontreponemal titers to decline fourfold within 6 months), not by the appearance of new lesions in the weeks following therapy. 4

Antibiotic Treatment Regimens by Stage

Primary and Secondary Syphilis

Benzathine penicillin G 2.4 million units intramuscularly as a single dose is the first-line treatment, achieving 90-100% cure rates. 4, 5, 6

• For penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 14 days is the preferred alternative. 4, 5
• Tetracycline 500 mg orally four times daily for 14 days is an acceptable alternative, though adherence is generally better with doxycycline due to less frequent dosing. 4, 5
• Erythromycin 500 mg orally four times daily for 14 days is less effective and should only be used when strict compliance and reliable follow-up can be guaranteed. 5
• Azithromycin should NOT be used in the United States due to widespread macrolide resistance and documented treatment failures. 4, 5

Early Latent Syphilis (≤1 year duration)

Benzathine penicillin G 2.4 million units intramuscularly as a single dose. 4, 5

• Early latent syphilis is defined by documented seroconversion within the past year, unequivocal primary/secondary symptoms within the past year, or a sexual partner with confirmed early syphilis. 5
• For penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 14 days. 4, 5

Late Latent Syphilis and Syphilis of Unknown Duration

Benzathine penicillin G 7.2 million units total, administered as three weekly injections of 2.4 million units intramuscularly. 4, 5

• For penicillin-allergic non-pregnant adults, doxycycline 100 mg orally twice daily for 28 days. 4, 5
• A cerebrospinal fluid (CSF) examination must exclude neurosyphilis before using any non-penicillin regimen for late latent infection. 4, 5
• Lumbar puncture is recommended before therapy when any of these are present: neurologic or ophthalmic signs, evidence of active tertiary disease, prior treatment failure, HIV infection with late latent disease, or a nontreponemal titer ≥1:32. 4, 5

Neurosyphilis

Aqueous crystalline penicillin G 18-24 million units per day intravenously (administered as 3-4 million units every 4 hours or continuous infusion) for 10-14 days is the standard therapy. 4, 5

• An alternative outpatient regimen is procaine penicillin 2.4 million units intramuscularly once daily PLUS probenecid 500 mg orally four times daily for 10-14 days, when adherence can be assured. 4, 5
• Procaine penicillin without probenecid is inadequate because it fails to achieve therapeutic CSF penicillin levels. 5
• Some experts add benzathine penicillin G 2.4 million units intramuscularly weekly for up to 3 weeks after completing the IV course to provide comparable total duration of therapy. 4, 5
• Ocular manifestations (uveitis, neuroretinitis, optic neuritis) must be managed as neurosyphilis, regardless of the stage suggested by other clinical features. 4, 5
• If CSF pleocytosis was present initially, repeat CSF examination every 6 months until cell count normalizes; consider retreatment if cell count has not decreased after 6 months or CSF is not normal after 2 years. 4, 5

Treatment in Pregnancy

All pregnant women with syphilis must receive the penicillin regimen appropriate for their disease stage—no exceptions. 1, 4, 5

• Parenteral penicillin G is the only therapy with documented efficacy for preventing congenital syphilis and treating fetal infection. 1, 4, 5, 7
• Treatment must occur more than 4 weeks before delivery for optimal outcomes. 4, 5
• For primary, secondary, or early latent syphilis, some experts recommend an additional dose of benzathine penicillin G 2.4 million units intramuscularly one week after the initial dose, especially in the third trimester or when treating secondary syphilis. 4, 5
• Pregnant women who miss any dose of the weekly benzathine penicillin series must repeat the entire course of therapy. 4, 5

Penicillin Allergy in Pregnancy

All pregnant patients with penicillin allergy must undergo desensitization followed by penicillin treatment. 1, 4, 5, 7

• Skin testing should be performed before desensitization. 4, 5
• Tetracyclines are contraindicated in pregnancy because they cause maternal hepatotoxicity and fetal bone-and-tooth staining. 5
• Erythromycin does not reliably eradicate fetal infection and should never be used in pregnant patients with syphilis. 5
• Azithromycin and ceftriaxone are inadequate alternatives because they do not reliably cure fetal infection. 4, 5

Jarisch-Herxheimer Reaction in Pregnancy

Women treated during the second half of pregnancy are at risk for premature labor or fetal distress from Jarisch-Herxheimer reaction. 4, 5

• Patients should seek immediate medical attention if they experience uterine contractions or reduced fetal movements within 24 hours of therapy. 4, 5
• For pregnancies >20 weeks gestation, consider fetal and uterine-contraction monitoring for 24 hours after initiating therapy, especially when ultrasound suggests fetal infection. 4
• Do not delay penicillin treatment because of fear of this reaction; untreated syphilis poses a far greater fetal risk. 4
• Up to 40% of fetuses with in-utero exposure to untreated syphilis are stillborn or die from their infection during infancy. 2

Treatment in HIV-Infected Patients

HIV-positive individuals should receive the same penicillin regimens as HIV-negative patients for all disease stages. 4, 5

• More intensive monitoring is required: clinical and serological evaluation at 3,6,9,12, and 24 months after treatment. 4, 5
• For late latent syphilis in HIV-infected patients, consider CSF examination before treatment to exclude neurosyphilis. 4, 5
• If nontreponemal titers do not decline fourfold within 3 months for primary/secondary syphilis, perform CSF examination and consider retreatment. 4
• When CSF is normal after treatment failure, most experts retreat with benzathine penicillin G 7.2 million units (three weekly doses of 2.4 million units each). 4, 5
• Efficacy of doxycycline or tetracycline as alternatives in HIV-infected patients has not been studied; use with extreme caution. 5

Jarisch-Herxheimer Reaction Management

The Jarisch-Herxheimer reaction is an acute febrile reaction—often accompanied by headache, myalgia, and other symptoms—that may occur within the first 24 hours after any therapy for syphilis. 1, 4, 5

• This reaction occurs most commonly among patients who have early syphilis. 1
• Continue penicillin therapy and provide supportive care, including antipyretics. 8
• No proven methods prevent this reaction, though antipyretics may be recommended. 1
• Patients should be advised of this possible adverse reaction before initiating treatment. 1, 4, 5

Follow-Up and Treatment Success Monitoring

Primary and Secondary Syphilis

• Perform quantitative nontreponemal serologic tests (RPR or VDRL) at 6 and 12 months after treatment. 4, 5
• Treatment success is defined as a fourfold (two-dilution) decline in nontreponemal test titers within 6 months. 4, 5
• Sequential RPR tests should use the same method and ideally the same laboratory, as RPR titers are often slightly higher than VDRL titers and cannot be directly compared. 4

Latent Syphilis

• Perform quantitative nontreponemal tests at 6,12,18, and 24 months after treatment. 4, 5
• A successful serologic response is defined as a fourfold decline in titers within 12-24 months. 4, 5

Treatment Failure Indicators

Retreatment is indicated if any of the following occur: 4, 5

• A fourfold increase in nontreponemal titers compared with the post-treatment nadir
• An initial titer ≥1:32 that fails to decline fourfold within 6-12 months for early syphilis or 12-24 months for late syphilis
• Development of new clinical signs or symptoms attributable to syphilis

When treatment failure occurs, re-evaluate for HIV infection and perform CSF examination unless reinfection is likely. 4, 5 If CSF is normal, retreat with benzathine penicillin G 7.2 million units (three weekly doses). 4, 5

Management of Sexual Partners

Persons exposed within 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively, even if seronegative. 1, 8

• Use benzathine penicillin G 2.4 million units intramuscularly as a single dose for presumptive treatment. 8
• Persons exposed more than 90 days before diagnosis should be treated presumptively if serologic test results are not available immediately and reliable follow-up cannot be ensured. 1, 8
• Time windows for presumptive treatment: 3 months plus duration of symptoms for primary syphilis, 6 months plus duration of symptoms for secondary syphilis, and 1 year for early latent syphilis. 5

Critical Pitfalls to Avoid

• Never use oral penicillin preparations for syphilis treatment—they are ineffective. 5, 8
• Do not use azithromycin in the United States due to widespread resistance. 4, 5, 8
• Do not substitute erythromycin, tetracyclines, azithromycin, or ceftriaxone for penicillin in pregnant women—they do not prevent congenital syphilis. 4, 5
• Do not switch between VDRL and RPR when monitoring serologic response—results cannot be directly compared. 4, 5
• Do not rely solely on treponemal test antibody titers to assess treatment response—they correlate poorly with disease activity. 5
• All patients diagnosed with syphilis should be tested for HIV if their status is unknown. 4, 5, 2