What is the best treatment for a cold sore (herpes simplex labialis) on the outside of the mouth?

Best Treatment for Cold Sores (Herpes Labialis)

Valacyclovir 2g twice daily for 1 day is the best treatment for cold sores, and you must start it within 24 hours of symptom onset—ideally during the prodromal stage (tingling, itching, burning)—to achieve maximum benefit. 1, 2, 3

Why Valacyclovir is First-Line

• Valacyclovir has the strongest evidence base, reducing median episode duration by 1.0 day compared to placebo in high-quality randomized controlled trials 1, 4
• The FDA has approved valacyclovir specifically for cold sore treatment in adults and children ≥12 years 3
• It offers superior convenience with just two doses taken 12 hours apart, compared to other oral antivirals that require multiple daily doses 1, 2
• Valacyclovir has 3-5 times higher bioavailability than acyclovir, achieving higher systemic drug concentrations that are more effective against the virus 4

Alternative Oral Antiviral Options

If valacyclovir is unavailable or not tolerated, use these alternatives in order of preference:

• Famciclovir 1500mg as a single dose - equally effective with the convenience of one-time dosing 1, 2
• Acyclovir 400mg five times daily for 5 days - effective but requires more frequent dosing that may reduce adherence 1, 2

Critical Timing: The 24-Hour Window

• Peak viral titers occur in the first 24 hours after lesion onset, making early treatment essential for blocking viral replication 1, 2
• Treatment initiated during the prodrome (tingling, itching, burning sensations before visible lesions) is most effective and may even prevent lesion development in some cases 1, 2
• Efficacy decreases dramatically once lesions have fully developed (vesicle, ulcer, or crust stages), so waiting is a critical mistake 1, 2
• The FDA label specifically notes that efficacy after clinical signs develop (papule, vesicle, ulcer) has not been established 3

What About Topical Treatments?

Avoid relying on topical antivirals as primary therapy—they provide only modest benefit and are significantly less effective than oral medications. 1, 2

• Topical penciclovir cream (FDA-approved) may reduce healing time by approximately 0.7 days, but this is inferior to oral valacyclovir's 1.0-day reduction 5, 6
• Topical treatments can be used as adjuncts for symptom relief but should not replace oral antivirals 2
• Consider white soft paraffin ointment applied every 2 hours for symptomatic relief 2
• Topical anesthetics (benzydamine hydrochloride) can help manage pain 2

When to Consider Suppressive Therapy

If you experience 6 or more cold sore outbreaks per year, you should be on daily suppressive therapy rather than treating individual episodes: 1, 2

• Valacyclovir 500mg once daily (can increase to 1000mg daily for very frequent recurrences) 1, 2
• Famciclovir 250mg twice daily 1
• Acyclovir 400mg twice daily 1, 2

Daily suppressive therapy reduces recurrence frequency by ≥75% among patients with frequent outbreaks 1, 2

Safety Profile

• All oral antivirals (valacyclovir, famciclovir, acyclovir) are generally well-tolerated with minimal adverse events 1, 2, 7
• Common side effects include headache (<10%), nausea (<4%), and mild diarrhea, which are typically mild to moderate in intensity 1
• Resistance to oral antivirals when used episodically in immunocompetent patients is extremely rare (<0.5%) 1, 2, 7

Common Pitfalls to Avoid

• Starting treatment too late - waiting until vesicles or ulcers appear significantly reduces efficacy 1, 2
• Using only topical treatments - this is the most common mistake, as oral therapy is far more effective 1, 2
• Not considering suppressive therapy - patients with ≥6 recurrences per year could benefit dramatically but often aren't offered this option 1, 2
• Using topical antivirals for suppression - these cannot reach the site of viral reactivation in sensory ganglia and are completely ineffective for prevention 1, 2

Preventive Counseling

• Identify and avoid personal triggers: UV light exposure, fever, psychological stress, menstruation 1, 2, 7
• Use sunscreen or zinc oxide on lips to decrease recurrence probability 2
• Consider patient-initiated therapy by keeping medication on hand to start at first symptoms 1

Special Populations

• Immunocompromised patients may require higher doses or longer treatment durations and have higher resistance rates (7% vs <0.5%) 1
• Children ≥12 years can use the same valacyclovir regimen as adults 2, 7, 3
• Pregnant/breastfeeding patients should discuss risks and benefits with their provider, though oral antivirals are generally considered safe