US Pharm. 2007;32(3):16-23.

Herpes simplex labialis, also known as cold sores, is a common cause of perioral discomfort. This condition affects millions of Americans and is the source of numerous patient inquiries to pharmacists. Pharmacists should be able to recognize the condition, explain its etiology, and fully describe the various options for prevention and treatment.

Infective Agents
Herpes simplex labialis is usually caused by the herpes simplex virus, type 1 (HSV-1), whereas the most common causative agent of genital herpes is herpes simplex, type 2 (HSV-2). However, oral/genital sexual practices can allow the viral invaders to cross-infect, so that HSV-2 is responsible for herpes simplex labialis in 10% to 15% of cases, and HSV-1 is sometimes found to be causal for genital herpes.1-3

Prevalence and Manifestations
HSV-1 infection is ubiquitous, with 600,000 new cases developing each year.4 There is no cure, so an initial infection remains, without exception. The epidemiologic conclusion to be drawn from a medical condition with this natural history is that the prevalence can only increase with the age of a given population group. 5 Thus, for HSV-1, estimates of prevalence should include the age under consideration. For instance, the prevalence in young adults is 20% to 40%. Each year beyond age 29, another 1.5% of patients reportedly contract the infection, up to age 50.3 By age 70, the prevalence approaches 90%. 6,7

There are five stages of a cold sore, from initial manifestation to complete healing.8 The patient's first sign is the prodromal stage, experienced by 46% to 60% of patients.9 This stage consists of tingling, itching, inflammation, erythema, hypersensitivity, and/or soreness in the exact location where the lesion will erupt. In patients with recurrent herpes simplex labialis, the location is often the same from episode to episode, most commonly on the mucocutaneous junction of the upper and/or lower lip, known as the vermilion border.9,10 Occasionally, the skin in and around the nose or on the cheeks is the target.10 Patients may also experience fever and/or malaise during the prodromal period.10 The prodrome usually lasts for one to two days and ends when blisters appear, signaling the onset of the blister stage. The blisters are filled with clear, yellow fluid. Several separate blisters may appear to coalesce as more blisters appear in the intervening spaces.1,8 At the end of this stage, the lips may be virtually disfigured by a large crop of blisters. After approximately two days, the blisters begin to rupture, exposing an erythematous open wound that becomes gray in color.8 This is the weeping stage. Highly infective yellowish fluid oozes from the wounds for a day or so. The wounds are covered with yellowish crusts in the scabbing stage, which lasts for two to three days. The skin beneath the scabs continues to be painful and pruritic, and the scabs begin to break and bleed. Each episode of scab damage is followed by formation of a smaller secondary scab. As this stage slowly resolves, the patient enters the healing stage. Secondary scabs become progressively smaller and slowly slough to reveal pink skin that gradually assumes the appearance of the surrounding unaffected epidermis.1,8 The disease seldom leaves permanent scars. The usual duration of the condition is seven to 10 days, but it may persist as long as two weeks.4

Initial Herpes Simplex Infection
The initial viral tissue invasion occurs typically in childhood or adolescence. This primary infection is often asymptomatic and may not be noticed by the patient or parents.11,12 Other patients notice only fever.8 When perioral symptoms do occur with the primary infection, they usually manifest one to three weeks after tissue penetration.1 In these patients, this initial HSV-1 infection is often the most severe. Recurrences are usually less intense than the initial episode, perhaps as a result of antibody production.8

Transmission of HSV-1
Patients may wish to understand how HSV-1 was contracted, in the hope that their family members or significant others avoid the disease. Patients must understand that the condition is highly contagious. Although some stages (e.g., prodrome, early blister stage prior to rupture, blisters postcrust formation) may pose slightly less risk than others, the possibility of transmission is virtually always present.8,9,13 When the blisters rupture, the exudate that issues from them carries millions of pathogens. Thus, patients must be constantly attentive to the techniques that help prevent transmission.

Triggers of Recurrence
Approximately one third of patients who experience the initial HSV-1 lesion undergo recurrences. Lifelong recurrence is associated with the postinfection behavior of the viral invader. HSV-1 establishes nonreplicating dormancy in the nerve that innervates the area where the lesion developed, most often the trigeminal ganglion.3 Investigators have not fully elucidated the triggers that allow the virus to emerge from its dormant condition to cause a recurrence. Nevertheless, numerous factors have been identified, such as natural or artificial ultraviolet light (e.g., sunlight, tanning beds), lip chapping, lip trauma or abrasion, fever (probably the origin of the lay term "fever blister"), menstrual periods, fatigue, overexposure to wind, immunosuppression, the common cold, dental instrument irritation of intraoral tissues, tooth removal or other dental surgery, digestive problems, traveler's diarrhea, decompression of the trigeminal nerve, physical stress, and
pregnancy. 1,3,4,6-8

Preventing Outbreaks
To prevent an outbreak, it is important to avoid the triggers listed above. Prevention of HSV-1 transmission is of equal importance. Some patients shed the virus in the absence of active lesions, an occurrence that cannot be remedied.1 Patients who undergo an active outbreak must be constantly alert to ensure that the virus in the infective exudate does not touch others.1,14 They must never kiss another person, nor engage in oral/genital sexual activity. Furthermore, they must avoid oral contact with anything that might touch the lips or skin of another person before it is decontaminated. They must avoid sharing such objects as drinking glasses, coffee mugs, straws, washcloths, towels, spoons, forks, lip balms, and medication dosing devices. All infected objects must be washed in hot water; boiling water is the most protective. They must refrain from touching the lesions, since they may transfer the virus to their hands. During a typical day, the hands contact hundreds of surfaces, and the virus could reach an object that is picked up by another person. If that person touches their lips, an invasion of the lips is likely. Lesions should be washed gently with soap and water, but the washcloth used should be laundered immediately after contact, as it is also infective. It may be worthwhile to advise patients to utilize a one-time use towel that can be discarded to further reduce the chance of cross-infection.

Nonprescription Treatment
The pharmacist can refer patients with an active case of HSV-1 to the physician for an antiviral, such as Zovirax or Denavir. However, nonprescription products may also be helpful. Docosanol 10% cream (Abreva) is a primary product among them, containing the inactive ingredients benzyl alcohol and light mineral oil. It is the only FDA-approved nonprescription product able to shorten healing time and duration of symptoms, such as tingling, pain, burning, and itching.15 Docosanol is optimally applied during the prodrome stage at the first sensation of tingling but will still be helpful if the patient waits until a later stage. This product, applied five times daily to the face and lips in patients 12 and older, prevents fusion between plasma membranes and the HSV-1 virus envelope, reducing the risk of intracellular entry with subsequent viral replication. Its use may prevent the eventual emergence of resistant HSV-1 isolates. Patients should rub the cream in gently and completely and wash their hands both before and after application. It should not be applied in or near the eyes or directly into the mouth. To prevent cross-infection, tubes of docosanol should not be shared with anyone else. If the lesion worsens or fails to disappear after 10 days of use, the patient should discontinue use and seek a physician.

Numerous other nonprescription products, ranging from useful to potentially dangerous, are available for symptomatic treatment of cold sores.16 FDA-approved pain relievers include external analgesic/anesthetics, such as benzocaine, benzyl alcohol, camphor, dibucaine, diphenhydramine, dyclonine, juniper tar, lidocaine, menthol, phenol, pramoxine, resorcinol, and tetracaine. FDA-approved protectants (e.g., allantoin, calamine, petrolatum, zinc oxide, and cocoa butter) soften the skin to prevent cracking and also relieve dryness. Some products that include these ingredients are Anbesol Cold Sore Therapy (64.9% white petrolatum, 20% benzocaine, 3% camphor, 1% allantoin) and Neosporin LT (1.5% allantoin, 1% pramoxine).

Nonprescription Products to Avoid
Manufacturers have marketed many products without proof of safety and efficacy for HSV-1. Lysine is a standard remedy recommended by health food stores but lacks evidence of any effect on cold sores. Novitra is a cream with homeopathically diluted zinc oxide that also lacks safety and efficacy data. Releev contains benzalkonium chloride, an antiseptic agent not proven safe or effective for cold sores.

Carmex is labeled as containing the active ingredients menthol 0.7%, camphor 1.7%, and phenol 0.4%. However, packages also disclose that it contains salicylic acid as an "inactive ingredient." Salicylic acid is highly active in eroding surface skin, depending on the concentration. (Even 1.8% to 3% concentrations cause keratolysis in seven to 10 days.) Its legitimate nonprescription uses include destroying warts, corns, and calluses. In those conditions, the stratum corneum (upper epidermal layer) is hyperkeratotic, and salicylic acid safely erodes the abnormally thickened skin. Yet, since the lips have little or no stratum corneum, Carmex could cause damage if used for cold sores. Until the manufacturer discloses the concentration of salicylic acid in the product, its safety cannot be verified and the product should not be recommended.


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