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. 2009 Sep 23;2009:1704.

Herpes labialis

Graham Worrall 1
PMCID: PMC2907798  PMID: 21726482

Abstract

Introduction

Herpes simplex virus type 1 infection usually causes a mild, self-limiting painful blistering around the mouth, with 20% to 40% of adults affected at some time. Primary infection usually occurs in childhood, after which the virus is thought to remain latent in the trigeminal ganglion. Recurrence may be triggered by factors such as exposure to bright light, stress, and fatigue.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of antiviral treatments for the first attack of herpes labialis? What are the effects of interventions aimed at preventing recurrent attacks of herpes labialis? What are the effects of treatments for recurrent attacks of herpes labialis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to February 2009 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 27 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: oral antiviral agents, sunscreen, topical anaesthetic agents, topical antiviral agents, and zinc oxide cream.

Key Points

Herpes simplex virus type 1 infection usually causes a mild, self-limiting painful blistering around the mouth, with 20% to 40% of adults affected at some time.

  • Primary infection usually occurs in childhood, after which the virus is thought to remain latent in the trigeminal ganglion.

  • Recurrence may be triggered by factors such as exposure to bright light, stress, and fatigue.

Oral antiviral agents such as aciclovir may reduce the duration of pain and time to healing for a first attack of herpes labialis compared with placebo; however, evidence is limited.

Prophylactic oral antiviral agents may reduce the frequency and severity of attacks compared with placebo, but we don't know the best timing and duration of treatment.

  • We don't know whether topical antiviral treatments are beneficial as prophylaxis against recurrent attacks.

  • Ultraviolet sunscreen may reduce recurrent attacks; however, evidence is limited.

Oral antiviral agents may reduce the duration of symptoms and the time to heal in recurrent attacks of herpes labialis.

  • Oral aciclovir, famciclovir, and valaciclovir may marginally reduce healing time if taken early in a recurrent attack, but valaciclovir may cause headache.

We found limited evidence that topical antiviral agents may reduce pain and healing time in recurrent attacks. However, results are inconsistent and of marginal clinical importance.

We don't know whether topical anaesthetic agents or zinc oxide cream reduce healing time. Zinc oxide cream may increase skin irritation.

About this condition

Definition

Herpes labialis is a mild, self-limiting infection with herpes simplex virus type 1 (HSV-1). It causes pain and blistering on the lips and perioral area (cold sores); fever and constitutional symptoms are rare. Most people have no warning of an attack, but some experience a recognisable prodrome. In this review, we have included studies in people with normal immunity and excluded studies in people who are immunocompromised (e.g., studies in people with HIV or with cancer undergoing chemotherapy).

Incidence/ Prevalence

Herpes labialis accounts for about 1% of primary care consultations in the UK each year; 20% to 40% of people have experienced cold sores at some time.

Aetiology/ Risk factors

Herpes labialis is caused by HSV-1. After the primary infection, which usually occurs in childhood, the virus is thought to remain latent in the trigeminal ganglion. A variety of factors, including exposure to bright sunlight, fatigue, or psychological stress, can precipitate a recurrence.

Prognosis

In most people, herpes labialis is a mild, self-limiting illness. Recurrences are usually shorter and less severe than the initial attack. Healing is usually complete in 7 to 10 days without scarring. Rates of reactivation are unknown. Herpes labialis can cause serious illness in immunocompromised people.

Aims of intervention

To reduce the frequency and severity of recurrent attacks; to speed healing of lesions; to reduce pain, with minimal adverse effects.

Outcomes

Symptom improvement (severity of symptoms and duration of symptoms; does not include time to healing or crusting of lesions); time to healing (time to healing/time to crusting of lesions); rate of recurrence; quality of life; adverse effects of treatment.

Methods

Clinical Evidence search and appraisal February 2009. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2009, Embase 1980 to February 2009, and The Cochrane Database of Systematic Reviews, 2009, Issue 1 (1966 to date of issue). An additional search within the Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Herpes labialis.

Important outcomes , Adverse effects, Quality of life, Recurrence, Symptom improvement, Time to healing
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of antiviral treatments for the first attack of herpes labialis?
1 (20) Symptom improvement Oral antiviral agents versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for restricted population (children only)
1 (72) Time to healing Oral antiviral agents versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and incomplete reporting of results. Directness point deducted for restricted population (children only)
What are the effects of interventions aimed at preventing recurrent attacks of herpes labialis?
1 (147) Symptom improvement Oral antiviral agents versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (248) Time to healing Oral antiviral agents versus placebo 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and use of experimental exposure to artificial ultraviolet light
6 (752) Recurrence Oral antiviral agents versus placebo 4 –3 0 0 0 Very low Quality points deducted for incomplete reporting of results, exposure to artificial ultraviolet light in 1 RCT, and unclear outcome assessment
1 (90) Symptom improvement Topical antiviral agents versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for experimental exposure to artificial ultraviolet light
1 (90) Time to healing Topical antiviral agents versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for experimental exposure to artificial ultraviolet light
2 (271) Recurrence Topical antiviral agents versus placebo 4 –1 0 –2 0 Very low Quality point deducted for reporting of results. Directness points deducted for experimental exposure to artificial ultraviolet light and inconsistent results at different time points
2 (57) Recurrence Sunscreen versus placebo 4 –3 0 0 0 Very low Quality points deducted for sparse data, short follow-up, and use of experimental exposure to artificial ultraviolet light
What are the effects of treatments for recurrent attacks of herpes labialis?
3 (800) Symptom improvement Oral antiviral agents versus placebo 4 –2 –1 0 0 Very low Quality points deducted for incomplete reporting of results and unclear outcome assessment. Consistency point deducted for different results for different outcomes
4 (2482) Time to healing Oral antiviral agents versus placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for different results for different outcomes
5 (2588) Symptom improvement Topical antiviral agents versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
10 (4842) Time to healing Topical antiviral agents versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
1 (72) Symptom improvement Topical anaesthetic agents versus placebo 4 –2 0 –1 0 Very low Quality points deducted for sparse data and subjective outcome measure. Directness point deducted for unclear clinical relevance
1 (72) Time to healing Topical anaesthetic agents versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for unclear clinical relevance
1 (46) Time to healing Zinc oxide cream versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for limited outcomes reported (healing only)
1 (46) Adverse effects Zinc oxide cream versus placebo 4 –2 0 0 0 Low Quality points deducted for sparse data and no statistical comparison between groups
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2009 Sep 23;2009:1704.

Oral antiviral agents for first attack

Summary

Oral antiviral agents such as aciclovir may reduce the duration of pain and time to healing for a first attack of herpes labialis compared with placebo; however, evidence is limited.

Benefits and harms

Oral antiviral agents versus placebo:

We found two small RCTs in children. We found no RCTs in adults.

Symptom improvement

Oral antiviral agents compared with placebo Oral aciclovir may be more effective at marginally reducing the mean duration of pain in children of mean age 2 years with herpetic gingivitis–stomatitis of <4 days' duration (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Pain

RCT		 20 children, mean age 2 years, with herpetic gingivitis–stomatitis of less than 4 days' duration Mean duration of pain
4.3 days with oral aciclovir (200 mg 5 times daily)
5.0 days with placebo
P = 0.05 		Effect size not calculated oral aciclovir
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No data from the following reference on this outcome.

Time to healing

Oral antiviral agents compared with placebo Oral aciclovir may be more effective at reducing the median time to healing in children aged 1 to 6 years with herpes simplex gingivitis–stomatitis of <3 days' duration (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT		 72 children, aged 1 to 6 years, with herpes simplex gingivitis–stomatitis of <3 days' duration Median time to healing
4 days with oral aciclovir (15 mg/kg 5 times daily for 7 days)
10 days with placebo
Median difference 6 days
95% CI 4 days to 8 days 		Effect size not calculated oral aciclovir
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No data from the following reference on this outcome.

Recurrence

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 20 children of mean age 2 years with herpetic gingivitis–stomatitis of <4 days' duration Adverse effects
with oral aciclovir (200 mg 5 times daily)
with placebo

RCT		 72 children aged 1 to 6 years with herpes simplex gingivitis–stomatitis of <3 days' duration Adverse effects
with oral aciclovir (15 mg/kg 5 times daily for 7 days)
with placebo
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Further information on studies

None.

Comment

Oral aciclovir is excreted in breast milk. Aciclovir has been used to treat pregnant women with genital herpes, and one systematic review (search date 1996, 3 RCTs) found no evidence of adverse effects in women or newborn children (see antiviral treatment during pregnancy in the genital herpes review). However, evidence is limited and clinically important adverse effects cannot be ruled out.

Research in this area is difficult because people may not consult clinicians until they have experienced several attacks of herpes labialis.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Topical antiviral agents for first attack

Summary

We don't know whether topical antiviral agents can reduce pain or time to healing in a first attack.

Benefits and harms

Topical antiviral agents versus placebo:

We found no RCTs comparing topical antiviral agents versus placebo or no treatment.

Further information on studies

None.

Comment

Trials have found that topical aciclovir is associated with rash, pruritus, and irritation in some people, but no more frequently than placebo.

Research in this area is difficult because people may not consult clinicians until they have experienced several attacks of herpes labialis.

Substantive changes

No new evidence

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Oral antiviral agents to prevent recurrence

Summary

Prophylactic oral antiviral agents may reduce the frequency and severity of attacks compared with placebo, but we don't know the best timing and duration of treatment.

Benefits and harms

Oral antiviral agents versus placebo:

We found one systematic review (search date 2008),which included three RCTs and one pooled analysis of two further RCTs. We found one additional RCT. The review did not pool data and did not report a methodological appraisal or a statistical analysis of individual RCTs. Therefore, we have reported the RCTs from their original reports.

Symptom improvement

Oral antiviral agents compared with placebo Prophylactic oral aciclovir may be more effective at reducing the duration of symptoms in US skiers with a history of herpes labialis precipitated by ultraviolet light (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement

RCT		 147 US skiers with a history of herpes labialis precipitated by ultraviolet light
In review 		Duration of symptoms
with aciclovir (400 mg twice daily, starting 12 hours before ultraviolet exposure)
with placebo
P <0.05 		Effect size not calculated aciclovir
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No data from the following reference on this outcome.

Time to healing

Oral antiviral agents versus placebo Oral famciclovir may be more effective at reducing the mean time to healing in adults with a history of sun-induced recurrent herpes labialis (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Duration of lesions
with famciclovir (500 mg)
with placebo
Absolute results not reported
Reduction in healing time 2 days with famciclovir
P = 0.01 for famciclovir 500 mg v placebo 		Effect size not calculated famciclovir (500 mg)

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Duration of lesions
with famciclovir (125 mg)
with placebo
Absolute results not reported
Reported as not significant
P value not reported for famciclovir 125 mg v placebo 		Not significant

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Duration of lesions
with famciclovir (250 mg)
with placebo
Absolute results not reported
Reported as not significant
P value not reported for famciclovir 250 mg v placebo 		Not significant

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Size of lesions
with famciclovir (500 mg)
with placebo
Absolute results not reported
P = 0.04 for famciclovir 500 mg v placebo 		Effect size not calculated famciclovir (500 mg)

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Size of lesions
with famciclovir (125 mg)
with placebo
Absolute results not reported
Reported as not significant
P value not reported for famciclovir 125 mg v placebo 		Not significant

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Size of lesions
with famciclovir (250 mg)
with placebo
Absolute results not reported
Reported as not significant
P value not reported for famciclovir 250 mg v placebo 		Not significant
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No data from the following reference on this outcome.

Recurrence

Oral antiviral agents compared with placebo Prophylactic oral aciclovir may be more effective at reducing the frequency of attacks, but not at reducing lesion occurrence (not further defined). Oral famciclovir may be no more effective at reducing the number of lesions in adults with a history of sun-induced recurrent herpes labialis. Oral valaciclovir may be more effective at reducing the proportion of people with recurrence within 4 months and at increasing the time to recurrence in adults with a history of four or more attacks in the previous year (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Recurrence

RCT		 147 US skiers with a history of herpes labialis precipitated by ultraviolet light
In review 		Frequency of attacks
with aciclovir (400 mg twice daily, starting 12 hours before ultraviolet exposure)
with placebo
P <0.05 		Effect size not calculated aciclovir

RCT		 239 Canadian skiers with a history of recurrent herpes labialis
In review 		Lesion occurrence
21/93 (23%) with aciclovir (800 mg twice daily)
21/102 (21%) with placebo
P = 0.92 		Not significant

RCT		 20 people with recurrent herpes labialis
In review 		Clinical recurrences
with aciclovir (400 mg twice daily for 4 months)
with placebo
53% fewer attacks with aciclovir
P = 0.05 		Effect size not calculated aciclovir
98 adults with a history of 4 or more attacks in the previous year No recurrence 4 months
62% with oral valaciclovir 500 mg daily
40% with placebo
P = 0.041 		Effect size not calculated valaciclovir
98 adults with a history of 4 or more attacks in the previous year Mean time to recurrence
13.1 weeks with oral valaciclovir 500 mg daily
9.6 weeks with placebo
P = 0.016 		Effect size not calculated valaciclovir

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Number of lesions
with famciclovir (125 mg)
with famciclovir (250 mg)
with famciclovir (500 mg)
with placebo
Difference among groups reported as not significant (between group differences not assessed)
P value not reported 		Not significant
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Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 147 US skiers with a history of herpes labialis precipitated by ultraviolet light
In review 		Mild to moderate central nervous system or gastrointestinal tract adverse events
7/77 (9%) with aciclovir (400 mg twice daily, starting 12 hours before ultraviolet exposure)
3/76 (4%) with placebo
P = 0.34 		Not significant

RCT		 239 Canadian skiers with a history of recurrent herpes labialis
In review 		Rates of adverse events
58/115 (50%) with aciclovir (800 mg twice daily)
59/124 (48%) with placebo
P = 0.68 		Not significant

RCT		 239 Canadian skiers with a history of recurrent herpes labialis
In review 		Number of severe adverse events
5 with aciclovir (800 mg twice daily)
6 with placebo

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Headache or nausea (most common adverse events)
with famciclovir (125 mg)
with famciclovir (250 mg)
with famciclovir (500 mg)
with placebo
Absolute results not reported
Difference among groups reported as not significant (between group differences not assessed)
P value not reported 		Not significant

RCT
4-armed trial 		248 adults with a history of sun-induced recurrent herpes labialis Severe adverse events, within 30 days of the last dose of famciclovir
with famciclovir (125 mg)
with famciclovir (250 mg)
with famciclovir (500 mg)
with placebo
Absolute results not reported
98 adults with a history of 4 or more attacks in the previous year Adverse events
22 events in 33% of people with valaciclovir
29 events in 39% of people with placebo
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No data from the following reference on this outcome.

Further information on studies

None.

Comment

None.

Substantive changes

Oral antiviral agents to prevent recurrence One systematic review added (search date 2008),which did not pool data. It found three RCTs and one pooled analysis of two further RCTs that were already reported in this Clinical Evidence review. No new data added from the new review. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Topical antiviral agents to prevent recurrence

Summary

We don't know whether topical antiviral treatments are beneficial as prophylaxis against recurrent attacks.

Benefits and harms

Topical antiviral agents versus placebo:

We found one systematic review (search date 2008) identifying two RCTs. The review did not pool data, and did not report a methodological appraisal or a statistical analysis of individual RCTs. Therefore, we have reported the RCTs from their original reports. See harms under the effects of antiviral treatments for the first attack.

Symptom improvement

Topical antivirals compared with placebo We don't know whether prophylactic aciclovir cream is more effective than placebo cream at reducing the duration of pain in people with herpes labialis precipitated by exposure to sunlight (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Pain

RCT		 90 people, aged 18 years or older, with a history of herpes labialis precipitated by exposure to sunlight
In review 		Mean duration of pain
3.7 days with aciclovir cream
3.6 days with placebo cream
P >0.10
Results should be interpreted with care, as the RCT was conducted under artificial conditions 		Not significant
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No data from the following reference on this outcome.

Time to healing

Topical antivirals compared with placebo We don't know whether prophylactic aciclovir cream is more effective than placebo cream at reducing mean healing time in people with herpes labialis precipitated by exposure to sunlight (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT		 90 people, aged 18 years or older, with a history of herpes labialis precipitated by exposure to sunlight
In review 		Mean healing time to loss of crust
6.7 days with aciclovir cream
6.5 days with placebo cream
P = 0.79
Results should be interpreted with care as the RCT was conducted under artificial conditions 		Not significant

RCT		 90 people, aged 18 years or older, with a history of herpes labialis precipitated by exposure to sunlight
In review 		Mean healing time to normal skin
6.8 days with aciclovir cream
7.4 days with placebo cream
P = 0.70
Results should be interpreted with care, as the RCT was conducted under artificial conditions 		Not significant
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No data from the following reference on this outcome.

Recurrence

Topical antivirals compared with placebo We don't know whether prophylactic aciclovir cream is more effective than placebo cream at reducing recurrence in people with herpes labialis precipitated by exposure to sunlight (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Recurrence

RCT		 90 people, aged 18 years or older, with a history of herpes labialis precipitated by exposure to sunlight
In review 		People developing lesions
22/45 (49%) with aciclovir cream
18/45 (40%) with placebo cream
Significance not assessed
Results should be interpreted with care, as the RCT was conducted under artificial conditions

RCT		 196 skiers aged 18 years or over, with 3 episodes of sun-induced herpes labialis during the previous year
In review 		Proportion of people with lesions during the treatment period
15/91 (16%) with aciclovir cream
23/90 (26%) with placebo cream
P = 0.2 		Not significant

RCT		 196 skiers aged 18 years or over, with 3 episodes of sun-induced herpes labialis during the previous year
In review 		Proportion of people with lesions during the 4-day follow-up period after treatment
18/91 (20%) with aciclovir cream
35/90 (39%) with placebo cream
P <0.01 		Effect size not calculated aciclovir cream
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Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 90 people, aged 18 years or older, with a history of herpes labialis precipitated by exposure to sunlight
In review 		Adverse effects
with aciclovir cream
with placebo cream
Absolute results not reported

RCT		 196 skiers aged 18 years or over, with 3 episodes of sun-induced herpes labialis during the previous year
In review 		People reporting at least one adverse effect (not further defined)
15/95 (16%) with aciclovir cream
13/96 (14%) with placebo cream
Reported as not significant
P value not reported 		Not significant
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Further information on studies

None.

Comment

None.

Substantive changes

Topical antiviral agents to prevent recurrence One systematic review added (search date 2008), which identified two RCTs. The review did not pool data, and the results of the RCT were reported from the original papers. Benefits and harms section enhanced. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Sunscreen

Summary

Ultraviolet sunscreen may reduce recurrent attacks; however, evidence is limited.

Benefits and harms

Sunscreen versus placebo:

We found one systematic review (search date 2008) including one RCT of sufficient quality. We found one additional RCT.

Symptom improvement

No data from the following reference on this outcome.

Time to healing

No data from the following reference on this outcome.

Recurrence

Sunscreen compared with placebo Sunscreen may be more effective at decreasing the proportion of people with recurrence at 6 days (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Recurrence

RCT
Crossover design 		38 people with a history of recurrent herpes
In review 		Recurrence 6 days
0/35 (0%) with sunscreen
27/38 (71%) with placebo
P <0.001
Results should be interpreted with caution as crossover designs have important limitations 		Effect size not calculated sunscreen

RCT
Crossover design 		19 people exposed to a pre-established dose of ultraviolet light in a laboratory Recurrence at 6 days
1/19 (5%) with sunscreen
11/19 (58%) with placebo
P <0.01
Results should be interpreted with caution as crossover designs have important limitations and the RCT was conducted under artificial conditions 		Effect size not calculated sunscreen
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Quality of life

No data from the following reference on this outcome.

Adverse effects

No data from the following reference on this outcome.

Further information on studies

None.

Comment

None.

Substantive changes

Sunscreen One systematic review added (search date 2008)identifying one small crossover RCT already reported in this Clinical Evidence review. No new data added from the new review. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Oral antiviral agents for treating recurrent attacks

Summary

Oral antiviral agents may reduce the duration of symptoms and the time to heal in recurrent attacks of herpes labialis.

Oral aciclovir, famciclovir, and valaciclovir may marginally reduce healing time if taken early in a recurrent attack, but valaciclovir may cause headache.

Benefits and harms

Oral antiviral agents versus placebo:

We found one systematic review (search date 2008), which found five RCTs (published in 4 papers). The review did not pool data and did not report a methodological appraisal or a statistical analysis of individual RCTs. Therefore, we have reported the RCTs from their original reports.

Symptom improvement

Oral antiviral agents compared with placebo Oral aciclovir taken early in the attack (when the person first experiences tingling) may be more effective at reducing the duration of symptoms (not further defined) in adults with recurrent herpes labialis. Oral aciclovir taken within 12 hours of the onset of the first episode may be no more effective at reducing the duration of pain. We don't know whether oral famciclovir is more effective at reducing the median time to resolution of pain or tenderness in people aged 18 years or older with recurrent herpes labialis (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement

RCT		 174 adults with recurrent herpes labialis
In review 		Duration of symptoms
8.1 days with oral aciclovir (400 mg 5 times daily for 5 days)
12.5 days with placebo
P = 0.02 		Effect size not calculated oral aciclovir

RCT		 149 people
In review 		Mean duration of pain
1.31 days with aciclovir
1.35 days with placebo
Reported as not significant
P value not reported 		Not significant

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Median time to resolution of pain and tenderness
with famciclovir (as single dose on 1 day)
with placebo
Absolute results not reported
P <0.01 for famciclovir as single dose on 1 day v placebo
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details) 		Effect size not calculated famciclovir (as single dose on 1 day)

RCT		 701 people aged 18 years or older with recurrent herpes labialis
In review 		Median time to resolution of pain and tenderness
with famciclovir as two doses on 1 day
with placebo
Absolute results not reported
P = 0.54 for famciclovir as two doses on 1 day v placebo
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details) 		Not significant
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Time to healing

Oral antiviral agents compared with placebo Oral valaciclovir may be more effective at marginally reducing the median duration of the episode in people aged at least 12 years old with recurrent herpes labialis. Oral famciclovir may be more effective than placebo at reducing the median time to healing in people aged 18 years or older with recurrent herpes labialis, but not at increasing the proportion of people with aborted (not progressing beyond papule stage) lesions. Oral aciclovir taken within 12 hours of the onset of the first episode may be no more effective at reducing healing time (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT		 149 people
In review 		Mean healing time
7.78 days with aciclovir
8.64 days with placebo
Reported as not significant
P value not reported 		Not significant

RCT
3-armed trial 		902 people aged at least 12 years with recurrent herpes labialis
In review 		Median duration of episode
4.0 days with 1-day course of valaciclovir (2 g twice daily)
5.0 days with placebo
P <0.001 for 1-day course of valaciclovir v placebo 		Effect size not calculated oral valaciclovir

RCT
3-armed trial 		902 people aged at least 12 years with recurrent herpes labialis
In review 		Median duration of episode
4.5 days with 2-day course of valaciclovir (2 g twice daily for the first day followed by 1 g twice daily for the second day)
5.0 days with placebo
P = 0.009 for 2-day course of valaciclovir v placebo 		Effect size not calculated oral valaciclovir

RCT		 954 people aged at least 12 years with recurrent herpes labialis
In review 		Median duration of episode
5.0 days with 1-day course of valaciclovir (2 g twice daily)
5.5 days with placebo
P <0.001 for 1-day course of valaciclovir v placebo 		Effect size not calculated valaciclovir

RCT
3-armed trial 		954 people aged at least 12 years with recurrent herpes labialis
In review 		Median duration of episode
5.0 days with 2-day course of valaciclovir (2 g twice daily for the first day followed by 1 g twice daily for the second day)
5.5 days with placebo
P <0.001 for 2-day course of valaciclovir v placebo 		Effect size not calculated valaciclovir

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Median time to resolution of all vesicular lesions (primary and secondary lesions)
4.5 days with famciclovir as single dose on 1 day
6.6 days with placebo
P <0.001 for famciclovir as single dose on 1 day v placebo
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details) 		Effect size not calculated famciclovir

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Median time to resolution of all vesicular lesions (primary and secondary lesions)
4.1 days with famciclovir as two doses on 1 day
6.6 days with placebo
P <0.001 for famciclovir as two doses on 1 day v placebo
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details) 		Effect size not calculated famciclovir

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Proportion of people with aborted lesions (aborted lesions defined as herpetic lesions not progressing beyond the papule stage
with famciclovir as single dose on 1 day
with famciclovir as two doses on 1 day
with placebo
Absolute results not reported
Difference among groups reported as not significant
P value not reported
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details) 		Not significant
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Recurrence

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT
3-armed trial 		902 people aged at least 12 years with recurrent herpes labialis
In review 		Headache
9% with 1-day course of valaciclovir
9% with 2-day course of valaciclovir
4% with placebo
Significance not assessed

RCT
3-armed trial 		954 people aged at least 12 years with recurrent herpes labialis
In review 		Headache
10% with 1-day course of valaciclovir
9% with 2-day course of valaciclovir
5% with placebo
Significance not assessed

RCT
3-armed trial 		902 people aged at least 12 years with recurrent herpes labialis
In review 		Nausea
4% with 1-day course of valaciclovir
5% with 2-day course of valaciclovir
4% with placebo
Significance not assessed

RCT
3-armed trial 		954 people aged at least 12 years with recurrent herpes labialis
In review 		Nausea
4% with 1-day course of valaciclovir
4% with 2-day course of valaciclovir
5% with placebo
Significance not assessed

RCT
3-armed trial 		902 people aged at least 12 years with recurrent herpes labialis
In review 		Diarrhoea
4% with 1-day course of valaciclovir
3% with 2-day course of valaciclovir
3% with placebo
Significance not assessed

RCT
3-armed trial 		954 people aged at least 12 years with recurrent herpes labialis
In review 		Diarrhoea
2% with 1-day course of valaciclovir
1% with 2-day course of valaciclovir
3% with placebo
Significance not assessed

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Headache
9.7% with famciclovir as single dose on 1 day
7.3% with famciclovir as 2 doses on 1 day
6.7% with placebo
Absolute numbers not reported
Significance not assessed
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details)

RCT
3-armed trial 		701 people aged 18 years or older with recurrent herpes labialis
In review 		Nausea
2.2% with famciclovir as single dose on 1 day
2.3% with famciclovir as 2 doses on 1 day
3.9% with placebo
Absolute numbers not reported
Significance not assessed
Analysis included only people who subsequently developed vesicular herpes labialis lesions during the course of treatment, which may affect generalisability (see further information on studies for full details)
Open in a new tab

No data from the following reference on this outcome.

Further information on studies

In all, 701 people had symptoms of a recurrence and started study medication. However, the analysis only included the 477/701 (68%) of participants who subsequently developed vesicular herpes labialis lesions during the course of treatment. Hence, the results may only apply to those people who develop lesions, rather than all those people with initial prodromal symptoms.

Comment

We found no RCTs comparing early versus delayed intervention, therefore we can draw no firm conclusions about timing of treatment.

Substantive changes

Oral antiviral agents for treating recurrent attacks One systematic review added (search date 2008), which did not pool data. It identified four RCTs previously reported in this Clinical Evidence review, and one additional RCT comparing famciclovir versus placebo not previously reported in this Clinical Evidence review. Results from this RCT added from the original report of the RCT. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Topical antiviral agents for treating recurrent attacks

Summary

We found limited evidence that topical antiviral agents may reduce pain and healing time in recurrent attacks. However, results are inconsistent and of marginal clinical importance.

Benefits and harms

Topical antiviral agents versus placebo:

We found one systematic review (search date 2008), which found 12 RCTs (published in 11 papers) comparing topical aciclovir or penciclovir versus placebo. The review did not pool data, and did not report a methodological appraisal or a statistical analysis of individual RCTs. Therefore, we have reported the RCTs from their original reports.

Symptom improvement

Topical antiviral agents compared with placebo Topical aciclovir seems no more effective at reducing mean duration of pain. Topical penciclovir seems more effective at marginally reducing median duration of pain (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement

RCT		 61 people
In review 		Mean duration of pain
1.2 days with aciclovir
1.1 days with placebo
Significance not assessed

RCT		 30 people
In review 		Mean duration of pain
1.7 days with aciclovir
2.3 days with placebo
P = 0.53 		Not significant

RCT		 208 people
In review 		Mean duration of pain
1.9 days with aciclovir
2.1 days with placebo
P = 0.30 		Not significant

RCT		 2209 people
In review 		Median duration of pain
3.5 days with penciclovir cream (twice daily for 4 days)
4.1 days with control cream
P <0.001 		Effect size not calculated penciclovir cream

RCT		 80 people
In review 		Mean duration of pain
1.08 days with aciclovir
1.04 days with placebo
Significance not assessed
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No data from the following reference on this outcome.

Time to healing

Topical antiviral agents compared with placebo Topical aciclovir or topical penciclovir seem more effective at marginally reducing healing time (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT
Crossover design 		13 people
In review 		Mean healing time
7 days with aciclovir
8 days with placebo
P <0.05 		Effect size not calculated aciclovir

RCT		 30 people
In review 		Mean healing time
5.7 days with aciclovir
8.3 days with placebo
P = 0.022 		Effect size not calculated aciclovir

RCT		 45 people
In review 		Mean healing time
10 days with aciclovir
13 days with placebo
Reported as not significant
P value not reported 		Not significant

RCT		 208 people
In review 		Mean healing time
7.2 days with aciclovir
7.2 days with placebo
P = 0.67 		Not significant

RCT		 2209 people
In review 		Median healing time
4.8 days with penciclovir cream (twice daily for 4 days)
5.5 days with control cream
P <0.001 		Effect size not calculated penciclovir

RCT		 80 people
In review 		Mean healing time
7.9 days with aciclovir
8.8 days with placebo
Reported as not significant
P value not reported 		Not significant

RCT		 534 people
In review 		Mean healing time of lesions
7.6 days with 1% penciclovir
8.8 days with placebo
P <0.01 		Effect size not calculated penciclovir

RCT		 380 people
In review 		Mean healing time
9.0 days with aciclovir
10.1 days with placebo
P = 0.04
The RCT was conducted under artificial conditions 		Effect size not calculated aciclovir

RCT		 670 people
In review 		Mean healing time
4.3 days with aciclovir
4.8 days with placebo
P = 0.010 		Effect size not calculated aciclovir

RCT		 673 people
In review 		Mean healing time
4.6 days with aciclovir
5.2 days with placebo
P = 0.007 		Effect size not calculated aciclovir

RCT
3-armed trial 		31 people
In review 		Mean time to crusting
1.6 days with 5% aciclovir in a liposomal vehicle
4.8 days with control (drug-free vehicle)
P <0.05 		Effect size not calculated aciclovir in a liposomal vehicle

RCT
3-armed trial 		31 people
In review 		Mean time to crusting
4.3 days with 5% aciclovir cream
4.8 days with control (drug-free vehicle)
Reported as not significant
P value not reported 		Not significant
Open in a new tab

No data from the following reference on this outcome.

Recurrence

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 Adverse effects
with antiviral agents
with placebo
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Further information on studies

A total of 15 people in the RCT later took part in a crossover study, in which they received two forms of topical aciclovir (in random order) separated by a washout period of at least 1 month. The study found that aciclovir in liposomes significantly reduced the time to crusting of lesions compared with aciclovir cream (1.8 days v 3.5 days; P = 0.023). In this RCT, too few people experienced pain to enable statistical analysis of the impact of the treatments on discomfort.

Comment

We found no RCTs comparing early versus delayed intervention, therefore we can draw no firm conclusions about timing of treatment.

A number of the smaller trials comparing topical antiviral agents versus placebo found no significant effect of treatment. However, these studies may have lacked power to detect clinically important differences.

Substantive changes

Topical antiviral agents for treating recurrent attacks One systematic review added (search date 2008),which did not pool data and identified 12 RCTs already reported in this Clinical Evidence review. No new data from the systematic review added.Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Topical anaesthetic agents for treating recurrent attacks

Summary

We don't know whether topical anaesthetic agents reduce healing time.

Benefits and harms

Topical anaesthetic agents versus placebo:

We found one systematic review (search date 2008), which found no RCTs of sufficient quality. We found one additional RCT comparing 1.8% tetracaine (amethocaine) cream (applied 6 times daily until scab loss occurred) versus placebo.

Symptom improvement

Topical anaesthetic agents versus placebo Topical tetracaine may be more effective at increasing the proportion of people who subjectively rate the treatment as effective (measured on a 10-point scale); however, the clinical importance of this is unclear (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom improvement

RCT		 72 people Subjective treatment benefit index (patient-rated; scale of 1 to 10; 1 = no benefit at all, 10 = very effective treatment)
7.3 with 1.8% tetracaine cream
5.9 with placebo
P = 0.036
The clinical importance of these results is unclear 		Effect size not calculated tetracaine
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Time to healing

Topical anaesthetic agents versus placebo Topical tetracaine applied daily until scab loss occurs may be more effective at reducing the mean time to scab loss; however, the clinical importance of this is unclear (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT		 72 people Mean time to scab loss
5.1 days with 1.8% tetracaine cream
7.2 days with placebo
P = 0.002
The clinical importance of these results is unclear 		Effect size not calculated tetracaine
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Recurrence

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 72 people Adverse effects
with 1.8% tetracaine cream
with placebo
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Further information on studies

None.

Comment

None.

Substantive changes

Topical anaesthetic agents for treating recurrent attacks One systematic review added (search date 2008), which found no RCTs of sufficient quality. No data added from the new review. Categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2009 Sep 23;2009:1704.

Zinc oxide cream for treating recurrent attacks

Summary

We don't know whether zinc oxide cream reduces healing time. Zinc oxide cream may increase skin irritation

Benefits and harms

Zinc oxide cream versus placebo:

We found one systematic review (search date 2008), which found one RCT. The RCT compared zinc oxide/glycine cream versus placebo.

Symptom improvement

No data from the following reference on this outcome.

Time to healing

Zinc oxide cream compared with placebo Zinc oxide/glycine cream applied as soon as possible after the onset of an attack may be more effective at reducing time to healing (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Time to healing

RCT		 46 people
In review 		Time to healing
5.0 days with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
6.5 days with placebo
P = 0.018 		Effect size not calculated zinc oxide/glycine cream
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Recurrence

No data from the following reference on this outcome.

Quality of life

No data from the following reference on this outcome.

Adverse effects

Zinc oxide cream compared with placebo Zinc oxide/glycine cream may increase the risk of skin irritation (burning) compared with placebo (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects

RCT		 46 people
In review 		Transient mild to moderate sensations of burning
22% of people with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
7% of people with placebo
Absolute numbers not reported
Significance not assessed

RCT		 46 people
In review 		Itching
9% of people with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
4% of people with placebo
Absolute numbers not reported
Significance not assessed

RCT		 46 people
In review 		Stinging
3% of peolpe with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
4% of people with placebo
Absolute numbers not reported
Significance not assessed

RCT		 46 people
In review 		Tingling
3% of people with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
0% of people with placebo
Absolute numbers not reported
Significance not assessed

RCT		 46 people
In review 		Number of people who discontinued
with zinc oxide/glycine cream (applied twice hourly during waking hours as soon as possible after the onset of an attack)
with placebo
Absolute results not reported
Significance not assessed
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Further information on studies

None.

Comment

None.

Substantive changes

Zinc oxide cream for treating recurrent attacks One systematic review added (search date 2008),which identified one RCT previously reported in this Clinical Evidence review. No new data added from the review.Categorisation unchanged (Unknown effectiveness).

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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