Does topical urea improve treatment outcomes in onychomycosis?

Introduction

Onychomycosis is a challenging condition we frequently see in practice. It’s a topic I have discussed extensively on the website. In this blog, I am looking at a recent meta-analysis which assessed the safety and efficacy of adding topical urea into the treatment regime for fungal nail infection.

Physiology of urea in the skin

Urea is well recognised as a waste product in the body, but its role in normal epidermal physiology cannot be underestimated. Keratinocytes in the lower epidermal layers express specific urea transporters and other channels known as aquaporins. Importing urea into the keratinocytes creates a humectant effect - hydrating the cell and drawing in water through channels in the cell wall from the underlying dermis, maintaining cell turgidity and shape. It is this hydrating property, which is useful physiologically and potentially, therapeutically. Many emollients designed for the skin contain urea typically in the concentrations of around 5% to 20%, utilising its water retaining properties to improve skin hydration [1].

Above 25% concentration, its action becomes more keratolytic than hydrating [2]. The higher percentage formulations are used in the treatment of hyperkeratotic disorders of the skin. At  40% concentration, under occlusion, topical urea is able to dissolve the diseased keratin of nails. The first therapeutic use was described by Farber and South [3] in 35 patients and latterly by Baran & Dawber in the textbook, “Diseases of the Nail and Their Management” (published in 1984). Termed a “medical avulsion” it has been described as a means of debriding diseased nail in combination with antifungal treatments. The main advantage being its less invasive nature making it suitable where nail surgery maybe contraindicated such as those with ischaemia or limited healing capacity.

A toe with a Urea plaster in place

Urea as an aid in onychomycosis treatment

If you look at the treatment protocols for onychomycosis, for mild to moderate infections, topical agents such as 5% amorolfine lacquer are recommended. As with all topical treatments, their effectiveness relies significantly on the drugs ability to penetrate the nail to reach the nail bed where infection is often evident. Improving topical drug delivery can be afforded by nail reduction prior to topical treatment [4] or fenestration, creating a porous nail plate that allows topical drugs to reach nail bed infection [5].

Alternatively, topical urea has been employed as an adjunct in onychomycosis treatment as shown in previous case reports [6-8]. This was reviewed by Dars et al., in 2019 [9] who concluded that more research was required based on the limited evidence. Six years on, researchers have undertaken another systematic review of evidence to investigate its potential [10].

The authors undertook an extensive literature review and identified 12 studies which used randomised and non-randomised designs, that investigated topical 40% urea as an adjunct in laboratory confirmed onychomycosis. A combined 424 patients were treated with urea.

The study concluded that although 12 eligible papers were reviewed, the certainty of evidence was low. This was because of lack of blinding and high risk of bias in many studies. The randomised studies frequently lacked method reporting impacting reliability. Overall, the results concluded that addition of topical urea significantly improve the clinical cure rate over using an antifungal alone – meaning the nail improvement, by visual assessment only, improves. However,  the actual mycological cure rates showed no significant difference, suggesting nails may look slightly better but the fungus is still present in the nail.

In terms of safety, four studies did report any adverse effects. The most commonly reported were periungual maceration, desquamation, erythema, irritation, nail pain and ingrowing toenail.

What can we make of this?

As I report so often, the results only mean more work is needed in this area to truly assess the effectiveness of urea in onychomycosis. Amongst the patients in this review the diversity of nail infection was evident with some patients have total nail dystrophy, some proximal sub-ungual onychomycosis and other having the more common distal-lateral onychomycosis. This is a consideration as I have discovered myself using urea.

Practical application of 40% urea in podiatry

Urea (at 40%) is easily able to dissolve fungal-infected nail but is less effective at removing healthy nail – this may seem like a clinical advantage but to clarify, from my own experience, as the urea is applied topically, it does not work as well for sub-ungual infection. This is because the overlying nail plate is generally healthy and tougher, so the urea works less effectively. Of course, reduction with a drill prior to treatment can help but its reduced effectiveness in this presentation may warrant more specific research.

After a nail is dissolved, another consideration is whether antifungal medication should be continued to clear infection on the now exposed nail bed. Other studies have demonstrated, even after surgical avulsion of mycotic nails, topical antifungal agents may be required to clear residual infection for some time [11-13]. In addition, even if a nail can be chemically dissolved with urea it is not able to infiltrate the proximal nailfold where infection may still reside and consequently a new nail emerges it may already be infected with dermatophytes.

In the UK, 40% urea can be purchased by over the counter as Canespro® (Bayer). This is a kit containing a tube of 40% urea paste, plasters and nail files. In my own clinical experience, providing this at the clinic with nail reduction it enables the podiatrist to demonstrate the application of the urea and plasters. The patient then wears the plasters for around 24-48 hours before removing and reapplying the paste and re-covering it with the supplied plasters. Chemical avulsion for most takes around two to three weeks. Despite the product branding resembling Canesten®, it contains no medical anti-fungal agent. To be successful it’s important that the patient is agile enough to reach their feet and apply the treatment and plasters. In addition, the 40% paste is very stiff and can be difficult to squeeze from the tube.

In the UK, 40% urea is also available in some hand cream preparations, however in my experience, despite their significantly lower price, they are less effective for nail softening as they are more liquid and therefore more difficult apply and less likely to remain in situ on a nail to have a positive benefit. The Canespro® product is a stiff paste which stays in situ much more easily.

 

Authors Note: 

The author has received no financial incentives from any companies/suppliers of any mentioned products when writing this article.

References

1.            Bristow IR: Urea - the gold standard for emollients? Podiatry Now 2016, 19:20–23.

2.            Vidal I, Sanchez M, De la Cruz G, Trullas C, Galavany L, Marquez G, Umbert P: Using Urea at high concentrations: clinical cases. Poster EADV Spring Meeting, Paris; 2008.

3.            Farber EM, South DA: Urea ointment in the nonsurgical avulsion of nail dystrophies. Cutis 1978, 22:689–692.

4.            Malay DS, Yi S, Borowsky P, Downey MS, Mlodzienski AJ: Efficacy of debridement alone versus debridement combined with topical antifungal nail lacquer for the treatment of pedal onychomycosis: a randomized, controlled trial. J Foot Ankle Surg 2009, 48:294–308.

5.            Bristow IR, Baran R, Score M: Rapid Treatment of Subungual Onychomycosis Using Controlled Micro Nail Penetration and Terbinafine Solution. J Drugs Dermatol 2016, 15:974–978.

6.            Hardjoko FS, Widyanto S, Singgih I, Susilo J: Treatment of onychomycosis with a bifonazole-urea combination. Mycoses 1990, 33:167–171.

7.            Baran R, Coquard F: Combination of fluconazole and urea in a nail lacquer for treating onychomycosis. The Journal of dermatological treatment 2005, 16:52–55.

8.            Ishii M, Hamada T, Asai Y: Treatment of onychomycosis by ODT therapy with 20% urea ointment and 2% tolnaftate ointment. Dermatologica 1983, 167:273–279.

9.            Dars S, Banwell HA, Matricciani L: The use of urea for the treatment of onychomycosis: a systematic review. J Foot Ankle Res 2019, 12:22.

10.         Kurniasari FT, Ervianti E, Damayanti, Wungu CDK, Murtiastutik D, Indramaya DM, Anggraeni S, Avicenna F: Efficacy and Safety of 40% Urea as an Adjuvant to Antifungals for Onychomycosis: A Systematic Review and Meta-Analysis. Mycoses 2025, 68:e70097.

11.         Baden HP: Treatment of Distal Onychomycosis With Avulsion and Topical Antifungal Agents Under Occlusion. Arch Dermatol 1994, 130:558–559.

12.         Rollman O: Treatment of Onychomycosis by Partial Nail Avulsion and Topical Miconazole. Dermatologica 2009, 165:54–61.

13.         Hettinger DF, Valinsky MS: Treatment of onychomycosis with nail avulsion and topical ketoconazole. J Am Podiatr Med Assoc 1991, 81:28–32.