cold sores

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COLD SORES

MICHAEL BOIVIN, RPH, BSCPHM

COPYRIGHT

All rights, including copyright, in the content of the course are owned by the University of

Waterloo, Ontario Pharmacists Association and the authors, unless otherwise stated. The

use of the course material is for the registered student only. Not to be copied or distributed

without written permission from the University of Waterloo and Ontario Pharmacists

Association. Permission inquiries should be addressed to: [email protected].

ACKNOWLEDGMENT

The patient care wheel image used in the course was adapted (with permission) from the

JCPP’s Patient Care Process Graphic (https://jcpp.net).

LEARNING OBJECTIVES

• Describe pathophysiology of cold sores

• Identify possible causes and risk factors for cold sores

• Apply the elements of the Pharmacists’ Patient Care Process (PPCP) necessary for a

patient consultation on cold sores

SUGGESTED READINGS

1. St Pierre SA, Bartlett BL, Schlosser BJ. Practical management measures for patients

with recurrent herpes labialis. Skin Therapy Lett. 2009 Dec;14(8):1–3.

2. Raborn GW, Grace MG. Recurrent herpes simplex labialis: selected therapeutic

options. Journal-Canadian Dental Association. 2003;69(8):498–504.

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MEET OUR PATIENT – ALYSSA

Background

• 24 years old

• Retail worker at clothing store

• No medical conditions

• No known allergies

Current medications

• No current medications

Discussion

• She has heard that pharmacists can prescribe medications for cold sores and is

looking for a treatment that can help with her symptoms.

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BACKGROUND

Infection caused by herpes simplex virus (HSV) represents one of the more widespread

infections of the orofacial region.

1

HSV type 1 and type 2 (HSV-1 and HSV-2) are two strains

of the herpes virus that can infect humans.

1

HSV-1 infections primarily affect areas in the

facial region, where HSV-2 is primarily affects the genital area.

1

HSV-1 is the most common

cause of herpes labialis (commonly caused “cold sores” or “fever blisters”).

It is believed that the majority of Canadians will contract HSV-1 infection during childhood or

adolescence, with up to 80% of adults being seropositive for the virus.

2

Approximately one-

third of infected patients will develop relapses.

3

Patients with recurrent eruptions, will

normally have outbreaks one to six times per year.

4

Although most episodes of recurrent cold

sores are self-limiting and mild, frequent recurrences are associated with a significant impact

on health-related quality of life (HRQoL).

5

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Step 1: Collect

The first step of the minor ailment process is to find out more information regarding the patient

and their symptoms. Let’s watch our pharmacist Isabel engage Alyssa through the collection

process.

Pharmacist: “Sorry to hear you are getting a cold sore. Before I can make a

recommendation, I would need to get a bit more information. Is it ok with you if I ask you a

few questions about you and your symptoms?”

Alyssa: “Ok.”

Pharmacist: “Let’s start with a bit about your symptoms. You mentioned that you are getting

a cold sore. Can you tell me a bit more about the symptoms you have?”

Alyssa: “I get these stupid cold sores all the time. Whenever I am stressed, I feel this burning

and tingling, and I know that it is going to happen. That is what I feel right now. It started

today and I don’t want it to pop up.”

Pharmacist: “Ok. Do you have any other symptoms?”

Alyssa: “I am a little stressed with work but otherwise I am healthy.”

Pharmacist: “Any symptoms like pus or fever?

Alyssa: “No.”

Pharmacist: “You mentioned that you get these often when you are stressed. Can you

please tell me when it all started, how often you get them, and what they look like when

they flare?”

Alyssa: “Like I mentioned, I get this burning and tingling on my lips and after a few hours I

can start to see the blisters on my lips. After a few days they burst and look gross. At about

5-7 days they dry up and within 10 days everything goes back to normal. I would say I get

about 4 of these per year. I don’t know when they started, but I can remember them flaring

up when I started to go to high school.”

Pharmacist: “Thank you. What have you used to treat your cold sores?”

Alyssa: “I normally just apply rubbing alcohol to dry them out, but it really doesn’t help

much.”

Pharmacist: “Is there anything that makes them flareup besides stress?”

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Alyssa: “Yeah, if I stay out in the sun too long and they tend to come around my period.”

The SCHOLAR questions are designed to help gather the relevant information regarding the

patient’s condition. Let us look at the information the pharmacist collected from Alyssa.

•Burning and tingling at lip margin starting today

•She normally gets these symptoms prior to a cold

sore eruption

Symptoms

•Burning and tingling Characteristic of symptoms

•She has had these since high school

•Occur approximately 4 times per year

History of symptoms

•Symptoms start with burning/tingling, then

blisters erupt on lip, after a few days burst, crust

and then heal

Onset and timing of symptoms

•LipsLocation

•Stress, menstruation, ultraviolet (UV) radiation Aggravating factors

•None reported

•Tried rubbing alcohol, but did not help

Remitting factors

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The HAMS questions are designed to gather more information about the patient. Patient

factors are important to determine if the patient is appropriate for a minor ailment

assessment.

•None Health Conditions

•NoneAllergies

•NoneMedications

•Non-smoker

•Drinks alcohol socially and uses recreational

cannabis approximately every two weeks

Social history

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Step 2: Assess

CLINICAL PRESENTATION OF PRIMARY COLD SORES

Primary infection with HSV has two age-related peaks, the first in childhood (6 months to 5

years of age) and the second in the early twenties.

1

When it occurs in children, it tends to have

widespread oral ulceration. It is normally completely asymptomatic when it occurs in

adolescents and adults.

3

After primary infection, HSV-1 migrates along the nerve tracks from the oral mucosa to the

neuronal cell bodies.

6

Here a restricted replication of the cycle occurs, most often culminating

in a latent infection of the neurons.

1

The most common site of latency is in the trigeminal

ganglion and the infection remains for the life of the patient.

1

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CLINICAL PRESENTATION OF RECURRENT COLD SORES

Recurrent infections occur at variable intervals, ranging from months to years.

1

The recurrent

lesions occur at or near the site of primary infection and typically occur at a mucocutaneous

junction of the face, usually on the lips. The stages of recurrent cold sores are reviewed in the

table.

7

Most episodes of recurrent cold sores are self-limiting and mild.

8

The time from the prodrome

phase to healing without scarring occurs over a period of 1-2 weeks.

6

•60% of people have this approximately 6 hours

before lesion development

•Symptoms include: paresthesia, tenderness, pain,

tingling, itching

•Optimal timing for treatment

Prodrome

•The skin is red and raised due to inflammation

•Treatment at this stage is still optimal

Erythema

•Blisters are filled with viral laden fluid

•From blister rupture until crusts are shed will have

a reduced treatment effect

Papule, vesicle, ulcer and soft

crust

•Healing is occurring

•Residual erythema/inflammation of area can last

a longer period of time

Hard crust

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RISK FACTORS FOR HSV-1 INFECTION AND TRIGGERS FOR RECURRENT COLD SORES

Almost all adults will become infected with HSV-1 infection over the course of their life. It is

estimated that between 57% and 80% of adults are seropositive for HSV-1, with a greater

prevalence in those from lower socioeconomic status.

2

There are also a number of factors

that have been found to trigger a recurrence of cold sores. The table reviews some risk factors

for HSV-1 infection and common triggers for a recurrence.

Table 1. HSV-1 infection risk factors and common cold sore triggers

1,9

Risk factors for HSV-1 infection

Common triggers for cold sore recurrences

• Female gender

• Black race

• First intercourse occurred prior to or

at 15 years of age

• Greater total years of sexual activity

• History of a partner with oral sores

• Personal history of a non-HSV

sexually transmitted infection

• Fever

• Ultraviolet light exposure

• Viral upper respiratory tract infection

• Emotional stress

• Fatigue

• Trauma

• Iron deficiency

• Oral cancer therapy

• Immunosuppression and

chemotherapy

• Oral and facial surgery

• Vital infections

• Gastrointestinal upset

• Menstruation

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DIFFERENTIAL DIAGNOSIS AND ALARM FEATURES

The diagnosis of recurrent cold sores is usually straightforward and based on the reported

history, classic location and clinical appearance of lesions.

6

Pharmacists should consider

referral of patients not presenting with classic cold sore symptoms, those with signs of a

bacterial infection (e.g. pus, fever, etc.), immunocompromised patients, those having more

than 6 episodes per year and those who have not responded to prescribed therapy.

The table reviews the differential diagnosis of herpes labialis.

Table 2. Differential Diagnosis of HSV-1 Infection

4

Condition

Features

Diagnosis

Treatment

Aphthous

Ulcers

Individual erythematous

patches or plaques that

may have a central

vesicle, erosion or ulcer.

These ulcers are painful,

but the patient is

afebrile and not

otherwise ill

The cause remains

unknown, but is not viral

Clinical appearance: herpes

simplex virus culture will be

negative

Self-limiting, usually

no treatment

necessary; topical

steroids, if needed

Behҫet’s

Syndrome

Produces painful often

larger ulcerative disease

in the mouth and

genitals

Diagnostic criteria:

(aphthous) ulcers (any

shape, size, or number at

least 3 times in any 12

months period)

PLUS: 2 or more of

following:

• Genital or anal ulcers

• Skin lesions

• Eye inflammation

• Pathergy reaction (Skin

condition in which a

minor trauma such as a

bump or bruise leads to

the development of skin

lesions or ulcers that

may be resistant to

healing)

Tetracycline/minocy

cline/doxycycline

and topical steroids;

may need oral

prednisone and

immunosuppressive

agents

Herpangina

Oral infection with small

ulcers caused by

Coxsackie virus; ulcers

characteristically seen

Clinical presentation

Symptomatic

management

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on the soft palate.

Sudden onset of fever

Seen in children ages

three to 10 years

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Step 3: Plan

GOALS OF THERAPY

The goals of therapy of managing cold sores include:

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• Reducing any discomfort, including pain, tingling or itching. Treatment manages

outbreaks, but is not curative

• Reducing viral shedding

• Reducing the duration of lesions

• Reducing the severity of the episode

• Preventing secondary bacterial infection

• Preventing recurrences

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NON-PHARMACOLOGICAL TREATMENT

Trigger avoidance may help to reduce the risk of cold sore recurrences. As was reviewed

earlier, most of these triggers are not easily modifiable. One common trigger the patient can

address is UV radiation protection. The use of sunscreens on the face and lips may help

reduce the risk of recurrences.

HSV infections are highly contagious.

6

Patients should be educated on the infectious nature

of herpetic lesions and asymptomatic viral shedding and should avoid touching the lesions to

prevent the spread of HSV to other sites through autoinoculation or transmission to other

individuals.

6

Patients with active lesions should be encouraged to:

• Regularly wash their hands, particularly after application of topical medications; to

avoid kissing others; and to avoid sharing utensils.

6

• Keep the lesions clean with gentle washing using a mild soap and water.

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o This can also be accomplished by soaking the area with a cool cloth or gauze

compress with tap water.

10

• Use of ice packaged in a washcloth and analgesics such as acetaminophen or

ibuprofen may help to reduce the pain of herpes labialis.

10

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PHARMACOLOGICAL TREATMENT

There are two main groups of treatment options for the management of herpes labialis. They

can be broadly grouped into:

• Topical treatments (OTC and prescription)

• Oral antivirals

TOPICAL AGENTS (OTC)

Topical Anesthetics

There are a wide number of topical anesthetics marketed for cold sore relief. These products

contain ingredients such as benzocaine, lidocaine, pramoxine).

10

They do not affect the course

of the recurrence but can be used to reduce pain and itching.

10

Products containing lidocaine

and pramoxine are rare contact sensitizers. Topical benzocaine is a more frequent sensitizer

and should be avoided.

Docosanol

Docosanol cream is available over-the-counter (OTC) for the management of herpes labialis.

The active component interacts with and stabilize lipids in the target cell membrane, thus

making the cell resistant to HSV fusion and entry.

11

It is indicated for the treatment of perioral

skin only and its activity does not extend beyond the locally treated region of HSV recurrence.

11

Trials with 10% docosanol cream, applied 5 times a day for 10 days, reduced healing time

significantly by (1.6 to 4.6 days), with early treatment (in the prodrome and erythema stage)

having the most benefit.

8

The duration of pain symptoms was also reduced (2.2 versus 2.7

days).

4

Evidence suggests that 10% docosanol is effective in reducing the healing time and

pain in recurrent herpes labialis.

8

Additional OTC Agents

Additional over-the-counter products with limited evidence include the following active

ingredients:

• Propolis (honey extract)

• Combination of boric acid and benzoyl alcohol

• Combination product combining the cooling effect of menthol, phenol and camphor

with sodium/ calcium hydroxide

• Lysine

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TOPICAL AGENTS (PRESCRIPTION)

Although topical acyclovir is indicated for genital herpes simplex infections, it has been used

for many years for the treatment of recurrent episodes of herpes labialis. Trials with both a

5% and 10% formulation of acyclovir ointment failed to demonstrate any effect over placebo

in terms of lesion duration, pain duration or size of lesions.

8

Clinical trials with 5% acyclovir cream (in propylene glycol or modified aqueous base) applied

5 times per day for 5 days at the earliest onset of prodrome resulted in a significant reduction

in the duration of vesicles, time to crust formation and duration of lesions.

8

It has little effect

on reducing pain. Acyclovir penetration in the modified cream was 8 times higher than in the

ointment.

8

Topical acyclovir 5% with 1% hydrocortisone cream applied 5 times per day for 5 days was

found to prevent to reduce the number of patients who develop an ulcerative lesion and

improve healing time by 1.4 days compared to placebo.

12

Topical antiviral agents are well tolerated but are generally viewed as less effective than oral

agents.

ORAL ANTIVIRALS

Oral antiviral therapies have been used extensively for the management of recurrent cold

sores. The three oral antiviral treatment options available in Canada include acyclovir,

valacyclovir and famciclovir. The evidence supporting these agents in cold sores is reviewed

in the table below.

Table 3. Evidence supporting oral antivirals for herpes labialis

Acyclovir

Valacyclovir

Famciclovir

Treatment of

cold sores

• 200 mg five times daily

for 5 days had no effect

on duration of pain or

time to recovery.

13

• 400 mg five times daily

for 5 days started within

1 hour of the first sign or

symptom of recurrence,

did NOT reduce the

development of the

lesion but reduced the

mean healing time by 1

to 1.5 days and the

mean duration of pain by

1 to 1.5 days.

8,14

• 1000 mg twice a

day for 1 day

may abort lesion

development if

the drug is taken

in the prodrome

phase.

8

• 2000 mg BID for

1 day shortens

the duration of

cold sore

episodes (0.5 to

1 day reduction)

and pain (0.5 to

0.7 day

reduction).

15

• a single dose of

1500 mg or 750

mg twice per day

for 1 day within

one hour of

prodromal

symptoms onset

was found to

reduce healing

times (4.4 days

for single dose

and 4.0 days for

750 mg twice

daily versus 6.2

days for placebo)

16

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Prevention

of cold sores

• Daily prophylactic

therapy is moderately

effective at preventing

recurrent herpes

labialis.

17

• The doses commonly

used in the prevention

studies was 800 mg/day

in 2 or 4 equal doses.

17

• In one clinical trial, this

regimen resulted in a

53% reduction in the

number of clinical

recurrences.

4

• 500 mg daily for

4 months

demonstrated a

reduction in the

number of cold

sore outbreaks.

17

• No evidence of

efficacy in the

prevention of

recurrent herpes

labialis.

17