Treatments for Cold Sores: An Updated Review

Cold sores — sometimes referred to as fever blisters, oral herpes or herpes labialis — can be painful and embarrassing. They are caused by a contagious virus called herpes simplex.

The most common herpes viruses are herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). Typically, HSV-1 causes cold sores or fever blisters around the lips, and HSV-2 causes genital herpes. But both herpes viruses can cause infections in either area. Once a person is infected with HSV, the virus remains dormant in nerve cells in the skin and can reactivate, causing recurrent cold sores at unpredictable intervals.

Cold sores often are preceded by burning, itching, tingling or numbness in the area where the cold sore is developing. A mature cold sore often has a crust overlying a red, inflamed area. The live virus can be transmitted from person to person by direct contact, even by an infected person who does not have cold sores. In most people with normal immune systems, cold sores are a mild condition and heal on their own within several days; they are primarily a cosmetic problem.

The Food and Drug Administration (FDA) has approved five antiviral drugs to treat recurrent cold sores. These drugs have been proven to minimally shorten the duration of, but not to cure, HSV infections.

Penciclovir (DENAVIR)

Penciclovir is a prescription topical cream that was approved by the FDA in 1996 for treatment of cold sores.[1]

The effectiveness of penciclovir was assessed in two clinical trials that compared penciclovir cream with a placebo cream in subjects with a history of frequent cold sores.[2] Subjects applied either penciclovir or the placebo cream within one hour of the first sign or symptom of a cold sore and then every two hours while awake for four days. Both trials showed that penciclovir stopped cold sore pain about half a day sooner than placebo. Furthermore, the average time for cold sore healing was shortened in subjects taking penciclovir by about half a day compared with placebo (4.5 days versus 5 days, respectively).[3]

Adverse effects reported with penciclovir include swelling, pain, itching and redness at the application site; headache; and swelling in the mouth and throat.

Docosanol (ABREVA)

Docosanol is an over-the-counter topical cream approved by the FDA in 2000 for treatment of cold sores.[4] Upon examining the FDA’s review of the drug, we found it surprising that it was ever approved.[5] Three clinical trials failed to show a statistically significant difference in cold sore healing time for docosanol compared with placebo. In two of these trials, the cold sore healing time was slightly faster with placebo than with docosanol by a few hours. The third trial found that subjects receiving docosanol had cold sores resolve less than five hours faster than those receiving a placebo. The FDA medical officer and statisticians repeatedly recommended against the drug’s approval.

The manufacturer of docosanol later submitted data from additional studies to the FDA and, after some dispute, was able to convince the agency that two clinical trials yielded positive results in favor of docosanol over placebo.

Acyclovir (SITAVIG, XERESE, ZOVIRAX)

Acyclovir was initially approved by the FDA as a topical ointment and an injectable form under the brand name Zovirax in 1982 for the treatment of several types of herpes viral infections, but not cold sores in healthy people.[6] However, a topical cream form of Zovirax was approved in 2002 for the treatment of cold sores.[7],[8]

Two large clinical trials tested acyclovir cream in subjects with frequent cold sores. Subjects applied either acyclovir or placebo cream within an hour of symptom onset and then five times a day for four days. Both trials showed that acyclovir cream decreased the average duration of cold sores by half a day only compared with placebo (4.5 versus 5 days, respectively).[9]

In 2009, the FDA approved a combination topical cream containing acyclovir and the corticosteroid hydrocortisone under the brand name Xerese for treatment of cold sores.[10] A clinical trial of this product, which is applied five times per day for five days, showed that the subjects receiving the active drug experienced complete healing 1.6 days sooner and were less likely to develop an ulcerated cold sore.[11]

In 2013, that agency approved a tablet form of acyclovir under the brand name Sitavig for treatment of cold sores.[12] This drug, which is placed between the gum and lip and taken once, shortened the average duration of cold sores by half a day compared with a placebo.[13]

The most common adverse effects of topical acyclovir include skin and lip dryness, cracking, burning, itching and stinging.

Valacyclovir (VALTREX)

The oral drug valacyclovir was approved by the FDA in 2002 for the one-day treatment of cold sores.[14] The drug had previously been approved for the suppression and treatment of genital herpes and the treatment of shingles. Valacyclovir is rapidly converted in the body into acyclovir.

The 2002 approval was based on two large clinical trials that enrolled healthy adults and adolescents (12 years of age or older) with recurrent cold sores.[15] Patients self-initiated treatment at the earliest symptoms and prior to any signs of a cold sore, usually within two hours of symptoms occurring. The average duration of cold sore episodes was about one day shorter in subjects receiving valacyclovir than in those receiving a placebo. Gastrointestinal adverse effects, headache and rash were seen in clinical trials with the drug.

Famciclovir (generic only)

The oral drug famciclovir was approved by the FDA in 1994 under the brand name FAMVIR for the treatment of certain herpes infections and is currently only available in generic form. It was later approved in 2006 for single-dose treatment of cold sores.[16] That approval was based on a single clinical trial in adult subjects with recurrent cold sores. Subjects who took famciclovir experienced a reduced median healing time by nearly two days and faster pain relief by over one day as compared with subjects who took a placebo.[17]

The most common adverse effects of famciclovir are headache and nausea.

What You Can Do

If you have a cold sore, there are steps you can take to control discomfort, allow healing and avoid complications. The cold sore should be kept moist to prevent drying and cracking, which may allow bacterial infection to develop, thus delaying healing. Skin protectors such as petroleum jelly (VASELINE) will relieve dryness and keep the sores soft. Applying local pain relievers (anesthetics) containing drugs such as benzocaine can reduce discomfort. The cold sore should also be kept clean by gently washing with soap and water.

If you decide to use an FDA-approved antiviral drug for recurrent cold sores, oral famciclovir and topical acyclovir with hydrocortisone appear to offer the most benefit.
 

References

[1] Mylan Pharmaceuticals. Label: penciclovir cream (DENAVIR). November 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020629s019lbl.pdf. Accessed June 10, 2019.

[2] Ibid.

[3] Ibid.

[4] Food and Drug Administration. Approval letter for NDA 20-941. July 25, 2000. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/020941s000_Approv.pdf. Accessed June 7, 2019.

[5] Valacyclovir (VALTREX), Penciclovir (DENAVIR), and Docosanol (ABREVA) – How Much is One Day Without a Cold Sore Worth? Worst Pills, Best Pills News. January 2003. /newsletters/view/201. Accessed June 7, 2019.

[6] eMedExpert. Acyclovir (Zovirax). July 14, 2017. https://www.emedexpert.com/facts/acyclovir-facts.shtml. Accessed June 7, 2019.

[7] Food and Drug Administration. NDA 21-478 Approval Letter. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-478_Zovirax_Approv.pdf. Accessed June 7, 2019.

[8] Bausch Label. Label: acyclovir cream (ZOVIRAX). December 30, 2002. https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21478_zovirax_lbl.pdf. Accessed May 22, 2019.

[9] Ibid.

[10] Valeant Pharmaceuticals. Label: acyclovir and hydrocortisone cream (XERESE). January 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022436s004lbl.pdf. Accessed June 10, 2019.

[11] Ibid.

[12] Farmea. Label: acyclovir buccal tablets (SITAVIG). April 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203791s000lbl.pdf. Accessed June 10, 2019.

[13] Ibid.

[14] Food and Drug Administration. Approval letter for NDA 20-550/S-016. September 9, 2002. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/20550se1-016ltr.pdf. Accessed June 7, 2019.

[15] GlaxoSmithKline. Label: valacyclovir (VALTREX). 2003. https://www.accessdata.fda.gov/drugsatfda_docs/label/2003/020550s005lbl.pdf. Accessed June 7, 2019.

[16] Food and Drug Administration. Letter for NDA 20-363/S-027 and NDA 20-363/S-028. July 28, 2006. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2006/020363s027,%20020363s028LTR.pdf. Accessed June 7, 2019.

[17] Novartis Pharmaceuticals Corporation. Label: famciclovir (FAMVIR). December 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020363s050lbl.pdf. Accessed June 7, 2019.