Combination Treatments a Must for the War on Warts

Doug Brunk

March 08, 2022

When counseling patients with warts, Adam Friedman, MD, admits that he feels like a character from "Game of Thrones" since many treatment options are "medieval and painful," from duct tape occlusion to the stings of liquid nitrogen and salicylic acid.

"We can combine destructive, immunologic, and cytotoxic approaches," Friedman, professor and chair of dermatology at George Washington University, Washington, said at the ODAC Dermatology, Aesthetic & Surgical Conference. "It's not one or the other, we want to be aggressive. Combining therapies in the office and at home will accelerate clearance of warts; monotherapy just doesn't cut it."

At the initial clinic visit, he advises asking patients how long the warts have been present, because sometimes they will go away within a year or two without treatment. "If someone says, 'I've had these for years,' you know you're in for the long haul and you have to be aggressive with their therapy," Friedman said. "Sometimes you'll pick up plantar warts on a full-body skin exam and the patient may say, 'I really don't care. Please don't touch them,' so it's important to understand how they are impacting quality of life."

Patients should also be asked what treatments they have used previously, and it is important to set some realistic expectations and dispel some myths, Friedman said. "One of the most important things is that you must get these patients back. This is not often a one and done approach; you need to keep hitting them [with therapy], because if you let one infected keratinocyte survive, it's going to come back and it's still going to be contagious – more likely for that patient than for anyone else."

The application of liquid nitrogen is a popular, inexpensive destructive treatment option, with spray canisters that cost about $600. "You have to consider the temperature of the liquid nitrogen spray because melanocytes die at negative 5 degrees Celsius, so you have to be mindful in patients with darker skin tones that you may leave with permanent dyschromia, meaning hypopigmentation or depigmentation when you do this," he said. Because it is painful, "we're limited when it comes to treating children with warts who are younger than 9 or 10. I don't think the Q-tip method or dipping a hemostat in cryogen and touching the tip really works. You've got to create a nice ice ball that thaws and kills the infected keratinocytes."

Friedman favors a 10-second freeze of the wart, usually for two to three cycles depending on its anatomic location, and he may give patients imiquimod or 5-FU to use at home for 5 nights of the week. A recently published study found that the use of ultrasound gel increases the efficacy of cryotherapy in the treatment of warts.

Another destructive treatment approach is cantharidin 0.7% applied topically in the office. It is believed to activate neutral serine proteases that cause degeneration of the desmosomal plaque, leading to detachment of tonofilaments from desmosomes. Repeat in-office applications within 14-21 days may be necessary for this treatment, which is not approved by the Food and Drug Administration. "It is painless on application unless there's a break in the skin," Friedman said.

For warts on thicker areas such as palms and soles, he often employs combination therapy with cantharidin 1%, salicylic acid 30%, and podophyllotoxin 5%. "This can hurt a little bit, but some patients require only one treatment for cure," he said. "Efficacy depends on the size of the wart."

VP-102, a proprietary, drug-device combination product containing cantharidin, 0.7% "is coming down the pike," Friedman said. "From the data we have, it seems that pairing with a curette or a #15 blade first gets better penetration, which makes sense. Patients come back every 3-4 weeks for treatment. It is a big investment, but it is worth it. I tell patients it's not worth starting if you're not going to see it through. I tell them, 'we're going to see a lot of each other until this is clear.' "

As for immunomodulatory approaches, imiquimod 5% cream is approved for treating genital and perianal warts. In Friedman's clinical experience, it has limited efficacy on keratinized skin unless the surface has been disrupted, "so don't even waste your time unless you are using some approach to enhance skin penetration," he advised. "Insurance coverage can be a challenge," he added.

He recommends application with salicylic acid alternating with imiquimod 5% cream every night at bedtime – under occlusion for thicker skinned areas.

For patients who favor use of natural products, off-label ingenol mebutate is an option. A case series of its use in 17 patients with anogenital warts found that 16 experienced clearance of all warts treated with either 0.05% or 0.015% ingenol mebutate gel. Local irritation occurred within 24-48 hours and lasted 2-5 days.

A natural alternative treatment is Candida albicans skin test antigen (Candin), especially for cases of multiple lesions on the hands and feet, because a field effect can be achieved, Friedman said. "The idea here is simple. At most, you're talking about injecting a sentinel wart with 0.3 mL Candin 2-10 times every 3 weeks. The wart may be in a field of warts. That will induce an immune reaction that brings in the cavalry. I find that it works very well but it is painful, so when you're injecting the feet, get the foot positioned well, because that patient may inadvertently kick you in the face [upon injection]."

Authors of a recent systematic review and meta-analysis highlighted the efficacy for systemic retinoids in the treatment of warts, particularly recalcitrant or recurrent types (Dermatol Ther 2021 34[2]:e14793). "Tazarotene is going to be your best bet if you can get it," Friedman said. "If you have to go lower like OTC adapalene or tretinoin, be my guest, but tazarotene works best by slowing down that rapid turnover that the virus is imparting on the basal keratinocyte layer. It can enhance penetration of drug but also thin the warts out."

Friedman characterized human papilloma virus (HPV) vaccines, such as Gardasil 9, as "one of the greatest innovations" in the treatment of warts. While indicated as a preventive strategy, "it also works as treatment. I've had patients with recalcitrant genital warts who will clear after taking the vaccine. It is something to think about as an adjuvant to everything we do, because it can function as a treatment."

Another immunologic treatment option is the oral H2-receptor antagonist cimetidine taken 30 mg/kg per day for 3-5 months. "There is mixed evidence of efficacy with this," Friedman said. "I tend to use it in cases of innumerable flat warts."

As for cytotoxic options for treating warts, bleomycin works at 250-1,000 U/mL injected per lesion, with lidocaine. "This is painful to patients both on application and post treatment," he said. "But it works really well when used properly."

In one study of 46 patients who received intralesional bleomycin, 74% patients had complete resolution of all warts with an average of 1.7 treatments. About 70% of patients experienced pain that lasted less than 2 days after treatment. In a separate study of patients treated with bleomycin for warts, researchers in India diluted bleomycin with lidocaine to help mitigate some of that pain.

An additional cytotoxic option, 5-FU in formulations of 5% cream/solution or 1% cream, can effectively treat warts. Friedman typically suggests application to the affected area twice daily for 3-5 weeks. "The cost can be high especially for off-label use," he said. He noted that Skin Medicinals makes a compounded wart solution composed of 5% 5-FU and salicylic acid 30% solution. A 50 mL container sells for about $50.

Friedman had no relevant disclosures related to his presentation.

This article originally appeared on, part of the Medscape Professional Network.


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