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Topical 3% Diclofenac in 2.5% Hyaluronan Gel for the Treatment of Actinic Keratoses


J. K. Rivers, MD, FRCPC
Division of Dermatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Actinic Keratoses (AKs) are epidermal skin lesions that have the potential to develop into squamous cell carcinoma. Many of the treatment options available can cause discomfort, pain or skin irritation. Topical 3% diclofenac in 2.5% hyaluronan gel (Solaraze™, Bioglan Pharma) is a relatively new treatment that has been shown to be effective and well tolerated for the treatment of AKs.
Key Words: actinic keratoses, diclofenac, hyaluronic acid

Actinic Keratoses (AKs) are a relatively common premalignant inflammatory skin lesion, which affect a large proportion of individuals with light skin that has been exposed to sun and/or artificial UV radiation. Over a period of 10 years, a person with 8 AKs has a 6.1-10.2% chance of developing a squamous cell carcinoma.1 Risk factors for AKs include being:
• fair skinned
• male
• >50 years of age
• sensitive to the sun with poor ability to tan and frequent sunburns
• on a high fat diet
• immunosuppressed.2-6
AKs have a wide range of clinical presentations and there is no single therapy that treats the complete spectrum of pathologies and individuals. Current treatment options include cryosurgery, curettage, surgical excision, laser, chemical peels, photodynamic therapy (PDT), topical fluorouracil, and retinoids. Topical imiquimod has also been used experimentally.7 However, all these options have been associated with local discomfort and pain in some cases.8,9 Topical 3% diclofenac in 2.5% hyaluronic acid (Solaraze®, Bioglan Pharma) is a new treatment for AKs that has been approved in the US, Canada and several countries in the European Union.

Mechanism of Action

Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that is a potent inhibitor of inducible cyclo-oxygenase (COX-2), resulting in a reduction of prostaglandin synthesis.8 Sun damage and AKs have been linked with raised prostaglandins in exposed skin.10 Oral administration of this drug can result in adverse effects. However, when this gel is applied topically, diclofenac is absorbed into the epidermis, and studies indicate that systemic absorption is much lower than that occurring after oral daily dosing of this drug.10

Clinical Trials

In an open-label study of 29 patients with mild to severe AKs, 1.0gm of the gel was applied twice daily for up to 180 days (the median was 62 days). At the end of the treatment, lesions were scored using visual and photographic assessment. There was a highly significant (p<0.001) improvement in lesions with 48% showing a complete response. Thirty days post treatment, 27 of the patients were reassessed and those who had a complete response rose to 81% with another four (15%) showing marked clinical improvement.9

In a randomized double-blind, placebo controlled trial involving individuals with >5 AK lesions, adult patients received either 3% diclofenac gel in 2.5% hyaluronan gel or the gel vehicle as a placebo. They received 0.5gm b.i.d for 90 days. Assessments were made at each visit and 1 month posttreatment, and included Target Lesion Number Score (TLNS), Cumulative Lesion Number Score (CLNS) and Global Improvement Indices (GII). At the follow-up visit, 50% of the patients using diclofenac showed complete resolution of all target lesions using TLNS compared to 20% in the placebo group (p<0.001). With regard to CLNS, 47% of patients applying diclofenac showed complete resolution compared to 19% in the placebo group (p<0.001) and the GII showed a 79% improvement in the diclofenac group vs. 45% in the placebo group (p<0.001).11

Another multicenter, double-blind, placebo-controlled study of 195 patients received the same formulation of diclofenac, 0.5g or vehicle, twice daily for either 30 days or 60 days. While there was no statistical difference in complete responders in the 30 day treatment groups, significantly more patients given active treatment for 60 days had TLNS=0 (33% vs. 10%, p<0.05). With regard to CLNS, 31% of patients in the active group showed complete clearance vs. 8% for the placebo group (p<0.05). GII scores were also significantly better in the 60 day active treatment group (p<0.05).12

In a randomized, double-blind, controlled trial, 150 patients were asked to apply diclofenac 3% gel twice daily as well as a sunscreen once daily for 24 weeks. The complete response rates were 29% for the active gel and 17% for the control gel. The difference was not statistically significant (p=0.14).

Study n Treatment % Complete Response P
Open label study9 29 1.0gm applied b.i.d. for up to 180 days 81%* P<0.001
Randomized, double-blind, placebo controlled study11 96 0.5gm b.i.d. vs. placebo for 90 days 50% (TLNS) vs. 20% placebo*
47% (CLNS) vs. 19% placebo
P<0.001
P<0.001
Multicenter, double-blind, placebo-controlled12 195 0.5gm b.i.d. vs. placebo for 30 or 60 days 30 days:
14% (TLNS) vs.
4% placebo
60 days:
33% (TLNS) vs.
10% placebo*
30 days:
NS
60 days:
P<0.05
14% (CLNS) vs.
4% placebo
31% (CLNS) vs.
8% placebo*
NS P<0.05
Randomized, double-blind,
controlled trial13
150 Applied b.i.d. + sunsreen for 8-24 weeks 29% vs. 17% placebo P=0.14

Furthermore, a high percentage of patients in both groups experienced a partial response to the treatment (38%) for the diclofenac group and 45% for the control group, but there was no significant difference in the spectrum of response between the two treatments (p=0.18).13 It should be noted that the patients used sunscreens and there was no follow-up assessment 30 days post-treatment.

Adverse Events

Generally, adverse events have been mild-to-moderate in severity. The most commonly reported adverse events include: pruritus, application site reactions, dry skin, rash and erythema.

Conclusion

The primary cause of AKs is exposure to UV light. Wearing sun protective clothing, sunscreen and avoiding direct sunlight can help prevent them. However, for those patients who already have AKs, this new topical preparation provides an alternate therapeutic option. It has been shown to be effective, well-tolerated, and easy to administer.

References



  1. Topical 3% Diclofenac in 2.5% Hyaluronan Gel for the Treatment of Actinic Keratoses
  2. Laser Treatment of Scars