Interventions for treatment of herpes labialis (cold sores on the lips).

Abstract

Rationale: Herpes labialis (also known as cold sores or fever blisters) is a highly prevalent recurrent infection caused by the herpes simplex virus. Recurrences arise from varied triggers. Standard treatments usually involve nucleoside antivirals. Several studies have investigated alternative treatments such as zinc, honey, and photodynamic therapy for their potential to shorten lesion duration and relieve symptoms, but most reviews exclude these therapies. We wished to address this evidence gap by evaluating both conventional and alternative approaches, synthesising evidence on efficacy and safety to inform clinical practice and guide patient decisions.

Objectives: To assess the benefits and harms of interventions for treating herpes labialis in immunocompetent people.

Search methods: We searched CENTRAL, MEDLINE, and Embase on 23 September 2025, and we searched two clinical trial registries (ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform) on 1 October 2025.

Eligibility criteria: We included randomised controlled trials (RCTs) enrolling immunocompetent people with herpes labialis. Eligible interventions included topical, oral, and physical therapies (e.g. nucleoside antivirals, anti-inflammatory agents, phototherapy, photodynamic therapy). Eligible comparators were placebo, no treatment, or another active intervention. We applied no restrictions related to publication language or status (published, unpublished, in press, or in progress).

Outcomes: Our critical outcomes were healing time (with healing defined as loss of crusts or all symptoms), rated by participants or investigators; and any adverse events leading to treatment cessation. Our important outcomes were participant-rated improvement of signs and symptoms (e.g. global rate of change scales), change from baseline in clinical episode severity (e.g. lesion size), change from baseline in pain severity, and any mild or moderate adverse events not leading to treatment cessation.

Risk of bias: We assessed the risk of bias using the Cochrane RoB 2 tool.

Synthesis methods: We synthesised outcomes descriptively and pooled data with a random-effects meta-analysis using the inverse-variance method where appropriate. We reported dichotomous outcomes as risk ratios (RRs), continuous outcomes as mean differences (MDs), and time-to-event data as hazard ratios (HRs), all with 95% confidence intervals (CIs). For rare outcomes, we calculated the Peto odds ratio (OR). We assessed heterogeneity using the I² statistic and performed subgroup analyses by intervention or dose. We also conducted sensitivity analyses, excluding trials with high risk of bias. We rated the certainty of evidence using the GRADE approach.

Included studies: We included 87 RCTs with 22,631 participants. Forty-two trials were conducted in multiple centres and 39 in a single centre (the remaining 6 trials did not report number of centres). Most participants were adults (≥ 18 years), though some trials also enrolled younger individuals. The trials covered 58 interventions: 37 topical, eight oral, and 12 other therapies. Forty-three trials were industry funded, 25 received funding from non-profit organisations, one received no funding, and 18 did not report funding sources.

Synthesis of results: No studies in our main comparisons reported participant-rated improvement of signs and symptoms, change from baseline in clinical episode severity, or change from baseline in pain severity. Topical aciclovir versus placebo Topical aciclovir probably reduces healing time compared with placebo (MD -0.88 days, 95% CI -1.43 to -0.33; I² = 74%; 7 studies, 3475 participants; moderate-certainty evidence). The risk of adverse events leading to treatment cessation and the risk of mild or moderate adverse events are probably similar with topical aciclovir and placebo. Topical penciclovir versus placebo Topical penciclovir probably reduces healing time compared with placebo (MD -1.20 days, 95% CI -1.80 to -0.60; 528 participants; moderate-certainty evidence). The risk of adverse events leading to treatment cessation and the risk of mild or moderate adverse events are probably similar with topical penciclovir and placebo. Oral aciclovir versus placebo Oral aciclovir may result in little to no difference in healing time compared with placebo (MD -0.86 days, 95% CI -2.02 to 0.3; 1 study, 145 participants; low-certainty evidence). No studies in this comparison reported data for adverse effects. Oral valaciclovir versus placebo Oral valaciclovir reduces healing time compared with placebo (MD -1.05 days, 95% CI -1.40 to -0.70; P < 0.001, I² = 0%; 2 studies, 1218 participants). The trials evaluating this comparison reported no adverse events leading to treatment cessation. The risk of mild or moderate adverse events is probably similar with oral valaciclovir and placebo. Topical penciclovir versus topical aciclovir Topical penciclovir and topical aciclovir may have similar effects on healing time (hazard ratio (HR) 0.88, 95% CI 0.67 to 1.16; 1 study, 225 participants; low-certainty evidence). The trial evaluating this comparison reported no adverse events leading to treatment cessation. The risk of mild or moderate adverse events may be similar with topical penciclovir and topical aciclovir. Topical aciclovir versus oral aciclovir No trials compared topical aciclovir with oral aciclovir.

Authors' conclusions: Compared with placebo, topical nucleoside antivirals (aciclovir and penciclovir) probably reduce cold sore healing time by about one day. A study that compared topical penciclovir with topical aciclovir found that they may have similar effects on healing time. For oral nucleoside antivirals, we found that oral aciclovir compared with placebo may have little or no effect on healing time, while oral valaciclovir reduces healing time by about one day. The clinical importance of all reported reductions in healing time is uncertain, as no minimally important difference has been defined for this outcome in herpes labialis. Severe adverse events were rare, and mild or moderate adverse events were uncommon. Adverse events were generally balanced between treatments. From an equity standpoint, most studies focused on adults, predominantly women, with limited East Asian and paediatric representation. Future research should address these gaps by including under-represented groups and standardising outcomes for robust comparisons. Developing core outcome sets for recurrent herpes labialis would enhance consistency, support evidence synthesis, and guide clinicians towards more effective, equitable treatments globally.

Funding: This review had no dedicated funding.

Registration: Protocol (2022) DOI: 10.1002/14651858.CD015216.