The results of this study showed silver sulfadiazine is effective in wound healing and reduces the healing time in comparison with the control group and conjugated estrogen. In this study, the effects were approximately similar in phenytoin, estrogen, and control groups and these treatments had no advantage over one another. To the authors’ knowledge, this comparison has not been made in the literature; most studies investigated the effects of only 1 of these agents on the process of wound healing.
Phenytoin. The mechanism of action of topical phenytoin in wound healing remains a subject for debate. According to several clinical trials,18-20 phenytoin promotes proliferation of myofibroblasts and fibroblasts, the production of the extracellular matrix and its proteins, and the activity of growth factors. Eventually, collagen synthesis is enhanced, resulting in increased wound strength. Phenytoin also decreases collagenase activity, edema, wound exudate, and bacterial load. In a study conducted by Hasamnis et al,2 excisional wounds in 20 male Wistar rats were divided randomly to the control group (A) that received no drug and the treatment group (B) that received 1% phenytoin cream on their wounds for 16 days. This study showed the average number of days required for complete epithelialization of wounds in group B (20.60 ± 1.51) was significantly less than the period required for complete epithelialization in group A (23.00 ± 2.26) (P = .0120). The experimental study by Mathew et al6 demonstrated phenytoin had a positive effect in fracture healing. Beigom Taheri et al21 divided 60 rats into 4 groups: group 1 served as the control and the wounds in groups 2, 3, and 4 were treated with 1% phenytoin cream, diode laser, and both phenytoin cream and diode laser, respectively. Histopathologic features of reepithelialization of wounds in these groups were compared; reepithelialization was complete in all animals of the 4 groups and a keratin layer was generated, but in the phenytoin group the healing process was slower. The result for the phenytoin-treated group was not better than in the control group, which was similar to current study results.
Estrogen. The discovery of the crucial role of estrogen in skin physiology resulted in the hypothesis that it may have an important role in wound healing.14-16 Several studies have demonstrated estrogen might be involved in wound healing in terms of altering the inflammatory response, enhancing reepithelialization, inducing granulation formation, modifying proteolysis, and balancing collagen biosynthesis and degradation.16 However, conflicting results were obtained in the research. In the review of histological process of wound healing in animals by Gal et al,17 significant augmentation of neovascularization associated with enhancement of collagen deposition was reported. In the clinical trial conducted by Ghazizadeh Hashemi et al,15 patients with traumatic wounds were divided to 2 groups of 15. The case group was treated with topical conjugated estrogen cream, while the control received Eucerin cream as a placebo. Wound area, healing rate, and required time for wound healing were compared, and no significant differences were found between the 2 groups for these factors. These findings are comparable with the current results. A clinical trial conducted by Asilian et al22 found topical estrogen resulted in slower wound healing in comparison with phenytoin and silver sulfadiazine, also similar to the results of the current study.
Silver sulfadiazine. Silver sulfadiazine is best known for its antibacterial properties. The application of silver sulfadiazine was associated with favorable results in surgical wounds, burns, and wound healing in systematic reviews9 and descriptive studies,10 albeit with conflicting results. A recent systematic review by Wasiak and Cleland23 reported silver sulfadiazine may prolong healing time and increase pain, although the authors noted the existing evidence was limited by small sample sizes and the heterogeneity of the patient population. In a large systematic review, Miller et al10 concluded data are lacking to either confirm or disprove the routine use of silver sulfadiazine for patients with partial-thickness burns or stasis dermatitis ulcers.
In the current study, the average time to healing in the silver sulfadiazine group was shorter than in the phenytoin group, although the difference was not statistically significant. These 2 substances appeared to have almost similar effects, a finding comparable to results of the in vivo study by Shamseddini et al.24 Furthermore, the authors of the current study found a significant decrease in the time to healing in the silver sulfadiazine group in comparison with the estrogen and control groups. Although the results of some studies9,10,25-27 support these findings, other in vivo and review studies found increased rates of healing were obtained with other agents such as argan oil,28 silver nanoparticles,29 Lithospermum officinale,30 and honey31 in comparison with silver sulfadiazine.