Topical treatments for cutaneous warts
Viral warts are a common skin condition, which can range in severity from a minor nuisance that resolve spontaneously to a troublesome, chronic condition. Many different topical treatments are available.
To evaluate the efficacy of local treatments for cutaneous non‐genital warts in healthy, immunocompetent adults and children.
We updated our searches of the following databases to May 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library, MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), LILACS (from 1982), and CINAHL (from 1981). We searched reference lists of articles and online trials registries for ongoing trials.
Randomised controlled trials (RCTs) of topical treatments for cutaneous non‐genital warts.
Data collection and analysis
Two authors independently selected trials and extracted data; a third author resolved any disagreements.
We included 85 trials involving a total of 8815 randomised participants (26 new studies were included in this update). There was a wide range of different treatments and a variety of trial designs. Many of the studies were judged to be at high risk of bias in one or more areas of trial design.
Trials of salicylic acid (SA) versus placebo showed that the former significantly increased the chance of clearance of warts at all sites (RR (risk ratio) 1.56, 95% CI (confidence interval) 1.20 to 2.03). Subgroup analysis for different sites, hands (RR 2.67, 95% CI 1.43 to 5.01) and feet (RR 1.29, 95% CI 1.07 to 1.55), suggested it might be more effective for hands than feet.
A meta‐analysis of cryotherapy versus placebo for warts at all sites favoured neither intervention nor control (RR 1.45, 95% CI 0.65 to 3.23). Subgroup analysis for different sites, hands (RR 2.63, 95% CI 0.43 to 15.94) and feet (RR 0.90, 95% CI 0.26 to 3.07), again suggested better outcomes for hands than feet. One trial showed cryotherapy to be better than both placebo and SA, but only for hand warts.
There was no significant difference in cure rates between cryotherapy at 2‐, 3‐, and 4‐weekly intervals.
Aggressive cryotherapy appeared more effective than gentle cryotherapy (RR 1.90, 95% CI 1.15 to 3.15), but with increased adverse effects.
Meta‐analysis did not demonstrate a significant difference in effectiveness between cryotherapy and SA at all sites (RR 1.23, 95% CI 0.88 to 1.71) or in subgroup analyses for hands and feet.
Two trials with 328 participants showed that SA and cryotherapy combined appeared more effective than SA alone (RR 1.24, 95% CI 1.07 to 1.43).
The benefit of intralesional bleomycin remains uncertain as the evidence was inconsistent. The most informative trial with 31 participants showed no significant difference in cure rate between bleomycin and saline injections (RR 1.28, 95% CI 0.92 to 1.78).
Dinitrochlorobenzene was more than twice as effective as placebo in 2 trials with 80 participants (RR 2.12, 95% CI 1.38 to 3.26).
Two trials of clear duct tape with 193 participants demonstrated no advantage over placebo (RR 1.43, 95% CI 0.51 to 4.05).
We could not combine data from trials of the following treatments: intralesional 5‐fluorouracil, topical zinc, silver nitrate (which demonstrated possible beneficial effects), topical 5‐fluorouracil, pulsed dye laser, photodynamic therapy, 80% phenol, 5% imiquimod cream, intralesional antigen, and topical alpha‐lactalbumin‐oleic acid (which showed no advantage over placebo).
We did not identify any RCTs that evaluated surgery (curettage, excision), formaldehyde, podophyllotoxin, cantharidin, diphencyprone, or squaric acid dibutylester.
Data from two new trials comparing SA and cryotherapy have allowed a better appraisal of their effectiveness. The evidence remains more consistent for SA, but only shows a modest therapeutic effect. Overall, trials comparing cryotherapy with placebo showed no significant difference in effectiveness, but the same was also true for trials comparing cryotherapy with SA. Only one trial showed cryotherapy to be better than both SA and placebo, and this was only for hand warts. Adverse effects, such as pain, blistering, and scarring, were not consistently reported but are probably more common with cryotherapy.
None of the other reviewed treatments appeared safer or more effective than SA and cryotherapy. Two trials of clear duct tape demonstrated no advantage over placebo. Dinitrochlorobenzene (and possibly other similar contact sensitisers) may be useful for the treatment of refractory warts.
Chun Shing Kwok, Sam Gibbs, Cathy Bennett, Richard Holland, Rachel Abbott
Plain language summary
Topical treatments for skin warts
Viral warts are a common skin disease, most frequently affecting the hands and feet, caused by the human papilloma virus. While warts are not harmful and usually go away in time without any treatment, they can be unsightly and painful. Warts on the soles of the feet are also called 'plantar warts' or 'verrucas'.
This review did not cover the treatment of genital warts, and it only considered the evidence provided by the results of randomised controlled trials.
Salicylic acid (SA), a cheap and easily‐available solution painted on to warts, had a definite but modest beneficial effect compared to placebo. It is effective for warts at all sites and has few adverse effects, but it may take several weeks of daily use to work.
Cryotherapy, usually using liquid nitrogen, is often used for the treatment of warts, but it is less convenient, more painful, and also more expensive. One study suggested that there is evidence that cryotherapy is better than SA for warts on the hands, but when we combined this study with our other results, we were unable to confirm this. We found that more aggressive cryotherapy appears to be more effective than gentle cryotherapy, but with an increased risk of adverse effects, such as pain, blistering, and scarring. We only looked at information from clinical trials of cryotherapy and not over‐the‐counter freezing treatments for warts, so we cannot say if these are as effective.
During the production of the last version of this review, duct tape had gained favour as it is a safe and simple treatment that is easy to apply; however, the trial on which this was based was relatively small. In this updated review, we found two further trials of duct tape that suggested that this treatment is not as effective as first thought.
Other treatments covered by this review include 5‐fluorouracil, dinitrochlorobenzene, intralesional bleomycin, intralesional interferon, photodynamic therapy, and intralesional antigen. None of these treatments are used commonly, even by skin specialists, and there is much less evidence for their effectiveness. The limited available evidence we do have suggests that some of these treatments may be effective and could therefore be used for warts that have not responded to simpler, safer treatments, such as salicylic acid or cryotherapy.
Overall, providing a useful idea of 'what works' from such a wide range of studies was difficult as many studies were of poor quality.
Chun Shing Kwok, Sam Gibbs, Cathy Bennett, Richard Holland, Rachel Abbott
Implications for practice
More recent data from trials of cryotherapy and SA have provided better evidence for the use of these treatments. The relatively high rate of cure in control groups supports the notion that no treatment and awaiting spontaneous resolution is a very reasonable option, especially for recently‐acquired warts that are not causing too much bother. Warts that do not resolve spontaneously after many months to a year are probably less likely to do so without treatment.
Salicylic acid appeared to be both effective and safe, but only modestly effective in terms of size of effect, and this is particularly true for plantar warts. Overall, the data for SA remains the most consistent.
The data on cryotherapy is more limited and less consistent, with only one trial (Bruggink 2010) showing it to be superior to placebo or no treatment, and this was only for warts on the hands; the same trial showed cryotherapy to be more effective than SA for hand warts.
The EVERT study (Cockayne 2011), which compared cryotherapy versus SA (with no placebo arm), showed that SA is similar in efficacy to cryotherapy for plantar warts.
No trial showed cryotherapy to be any more effective than placebo for plantar warts alone, and in view of this, the continued use of cryotherapy for plantar warts is highly questionable. Indeed, only one trial (Bunney 1971, of SA) showed any treatment to be effective compared to placebo for plantar warts, and even then the size of effect was modest. Thus, no treatment seems to be particularly effective for plantar warts.
Pooled data from all relevant trials involving the treatment of warts at all sites showed no significant difference between cryotherapy and placebo, but also no difference between cryotherapy and SA; the latter suggesting that cryotherapy can also, like SA, be modestly effective.
It is difficult to draw firm conclusions from all these contradictory data about the different roles of SA and cryotherapy, but it remains true that there is still only limited evidence to support the use of cryotherapy, especially considering it is a more painful, hazardous, and expensive treatment when compared with SA. On the other hand, even though there is less evidence for its effectiveness, cryotherapy may work where SA has failed, and data from one trial (Bruggink 2010) showed this to be the case for warts on the hands.
The limited data on adverse effects, such as pain and blistering, suggest that these are more common with cryotherapy than with SA. However, it is also important to point out that participant satisfaction data suggest that these adverse effects do not seem to worry participants. More aggressive cryotherapy appears to be more effective than gentle cryotherapy, but with an increased risk of adverse effects. There is some evidence that SA combined with cryotherapy is more effective than SA alone.
Good quality data for most other treatments are still lacking.
Evidence for the efficacy of intralesional bleomycin remains limited. Two more recent left‐right studies showed it to be more effective than cryotherapy, so taking into account the fact that caution is required when interpreting trials with this sort of design, there may be a place for bleomycin in selected people with refractory warts.
Topical immunotherapy with dinitrochlorobenzene, intralesional 5‐fluorouracil, topical zinc, and silver nitrate are not commonly‐used treatments. The limited available evidence suggest that these treatments may have a therapeutic effect, but none have any clear advantage over SA and cryotherapy. The limited data on dinitrochlorobenzene suggest that it might be substantially more effective than cryotherapy and SA (see Implications for research), and so, again, there may be a place for topical immunotherapy with dinitrochlorobenzene (or other contact sensitisers, such as diphencyprone or squaric acid dibutylester, now probably in more common use than DNCB for refractory warts in specialist centres). The risk of troublesome allergic contact dermatitis (in the personnel who apply treatment, as well as those treated) needs to be taken into account when considering this treatment.
There is insufficient evidence to support the use of topical 5‐fluorouracil, pulsed dye laser, photodynamic therapy, 80% phenol, 5% imiquimod cream, intralesional antigen, and topical alpha‐lactalbumin‐oleic acid.
Intralesional interferon did not appear to be effective.
There is no very convincing evidence that occlusive treatment with various types of duct tape is effective, and two relatively‐recent trials that were newly included (de Haen 2006; Wenner 2007) showed no significant difference in effectiveness between clear duct tape and placebo.
Implications for research
The problem of cutaneous warts lends itself well to randomised control trials because it is common and not‐life threatening.
Despite a large number of published trials, only a minority are properly randomised and have an overall low risk of bias.
This updated review highlighted an apparent difference in response to treatment of warts at different body sites. Plantar warts (on the soles of the feet) appear to be a particular challenge, and any new trials should either concentrate on one body site or recruit sufficient numbers of participants with warts at each site to produce statistically‐meaningful results.
A reasonable amount of data are now available for the most commonly‐used treatments of cryotherapy and SA, although many of the included trials are small and have a significant risk of bias. Furthermore, larger studies of these treatments compared with each other and with placebo (using standardised treatment regimens) would be helpful.
Second‐ and third‐line treatments are treatment for warts used after the initial treatment (first‐line treatment) has failed. Finding treatments for refractory warts, such as those which fail first‐line therapy, is a challenge. Data on many of the second‐ or third‐line treatments mentioned above for refractory warts showed no advantage over cryotherapy or SA (which are generally used as first‐line therapies). Perhaps the controlled studies with such first‐line topical therapies have not been performed (and moreover are unlikely to be performed) because, generally, such second‐ or third‐line treatments are reserved for those who have already failed first‐line therapies.
Good quality studies of the more hazardous second‐line treatments, such as intralesional bleomycin and topical immunotherapy (with dinitrochlorobenzene, diphencyprone, or squaric acid dibutylester), are definitely needed to provide clearer guidance for their use. Finally, the more 'surgical' treatments, such as photodynamic therapy, pulsed dye laser, and even the carbon dioxide laser (for which no randomised trials were found), require further study.
Trials using within‐participant randomisation (e.g. left and right randomisation) and using individual warts as the unit of analysis are fraught with statistical and biological difficulties (Altman 1997; Altman 2002) and should be discouraged. Quasi‐randomised studies where allocation may be made alternately on the basis of birth date or hospital number are easy to manipulate. We excluded quasi‐randomised studies from this review for that reason, and future studies should be conducted using adequate randomisation and allocation concealment methods, to minimise selection bias.
A reduced area or volume of warts is not a clinically‐relevant end point, and sustained clearance of warts after a reasonable follow‐up period of at least three months and preferably six months is to be encouraged as the standard end point. As none of the trials evaluated quality of life outcomes, quality of life issues related to treatment for warts remains an area that requires future research.
This review was updated in 2011 and will be updated as new trials become available.